University of Michigan - Targeting Virulence Regulators as a Novel Approach to Antibiotics for Shigellosis (America)
Start : November 2018 | Status : Complete
The scientists: Marija Miljkovic
The sponsor: University of Michigan
Foundation funding: The Foundation is providing £93,585 in support
GSK’s contribution: GSK will provide compounds for screening, consumables and expertise to perform the HTS and to select and prioritize the most promising hits. Biology and pharmacology support will be provided as well.
Project Description: Diarrheal diseases, such as shigellosis, are the second leading cause of death in children under five years old. Many strains of Shigella spp. are drug or multi-drug resistant. Genetic knock-out studies of the Shigella virulence pathway controlled by the AraC-family transcription factor VirF (required for infection, cell-to-cell spread and escape from macrophages) show that inactivation of VirF or other virulence factors eliminates, or significantly reduces, pathogenicity. Importantly, expression of virulence factors is not required for Shigella viability; therefore, targeting virulence factors is expected to lower the risk for resistance development in Shigella while not affecting normal, avirulent colonic microbiota. We have identified 5 hits from an HTS of ~150,000 small molecules that inhibit VirF expression of a reporter gene and reduce the invasion efficiency of Shigella in in vitro models of infection. One of these hits blocks VirF binding to DNA. Our goal in this proposal is to identify novel and potent chemical matter that block Shigella virulence to conduct a ‘hit-to-lead” campaign. We will screen compounds from GSK’s 1.7M compound library, perform confirmation and secondary assays probing mechanism of action, PK/Tox and in vitro efficacy. Compounds that inhibit VirF•DNA binding will be co-crystalized with the VirF DNA binding domain to enable a structure-based hit-to-lead campaign
Oxford University Clinical Research Unit- Hit discovery for new antimicrobials against Shigella spp. (Europe)
Start : April 2017 | Status : Complete
The scientists: Andrew Lim – Phat Voong Vinh
The sponsor: Oxford University Clinical Research Unit
Foundation funding: The Foundation is providing £174,038 in support
GSK’s contribution: GSK will provide facilities for HTS and compound collections to be screened. In addition, GSK will provide resources in kind for DMPK and safety profiling of the interesting hits identified.
Project Description: Our ultimate aim is to develop new drugs for the treatment of infections caused by Shigella spp. (a major cause of diarrhea in low-income countries) that work through novel mechanisms of action. Within this open-lab application we aim to carry out the following:
- Phenotypic screening against Shigella sonnei and Shigella flexneri 2a using chemically diverse compound libraries under a variety of conditions aiming, where possible, to mimic physiological conditions.
- Screening compound libraries against AMR isolates in the presence of antimicrobials to which they are resistant, aiming to identify compounds that restore antimicrobial activity
- Compound hits will be validated through assay against panels of clinical isolates, including newly emergent MDR strains.
- Validated hits will be profiled in various in vitro DMPK assays, such as solubility and metabolic stability. Preliminary safety assessment in silico and in vitro will be additionally performed, as well as hit expansion.
Oxford University - Structural biology and assays enabling β-lactams that target Mycobacteria tuberculosis (Europe)
Start : July 2017 | Status : Complete
The scientists: Jurgen Brem – Mariska de Munnik
The sponsor: Oxford University
Foundation funding: The Foundation is providing £177,625 in support
GSK’s contribution: - Determination of anti Mtb activity in vitro and in vivo. Oxford University does not have the capacity required for this work, therefore a collaboration with GSK TC is essential for the project.
- Supply of compounds for testing in assays and structural evaluation (Note initial work will focus on compounds already available, with focused medicinal chemistry being the subject of a new funding application.)
- Expertise in mechanistic chemistry (including modeling) to be used in inhibitor design possibly coupled to modeling
- Assistance in project management including via frequent (Skype / phone) meetings
- Expertise in identifying routes to pre-clinical and clinical candidates
- A desire to work together to secure future large-scale funding to develop -lactam / analogous compounds to be used for Mtb treatment
- The ability to work collaboratively with Oxford to rapidly follow up breakthrough results on new types of inhibitor.
Project Description: β-Lactams, including penicillins, cephalosporins and carbapenems, remain the most important antibiotics in use for treatment of Gram- and Gram+ bacteria, but their use is compromised by growing resistance, most importantly due to widespread β-lactamase dissemination. Mycobacteria tuberculosis (Mtb) has a higher mortality rate than any other infectious disease; however, β-lactams have traditionally not been effective in Mtb treatment. The paradigm that β-lactams are not useful for treatment of Mtb (including XDR Mtb) is based on the poor cell permeability/stability/oral use of ‘classical’ β-lactams (which poorly penetrate the cell-membrane) and the presence of a genetically encoded β-lactamase (BlaC) in Mtb. This paradigm is now being questioned [1-3], because: (i) Recent clinical trials shows that meropenem combined with amoxicillin–clavulanic acid has potential for treating Mtb; (ii) Carbapenems not only inhibit Mtb D,D-transpeptidases, but can also Mtb inhibit L,D-transpeptidases ; (iii) Clinically used cephalosporins in combination with clavulanic acid manifest synergistic effects in Mtb treatment; (iv) novel cephalosporins with C-2 carboxylate isosters have shown selective activity against non-replicating Mtb . Thus, the timing is right for focused efforts to develop tailored β-lactams for Mtb treatment together BlaC inhibitors, the latter being the initial focus of our proposed work.
Such work will be enabled by contemporary availability of: (i) New types of transpeptidase / β-lactamase inhibitors, including new acylating agents, such as those based on avibactam and lactivicins , and ‘transition state analogues’ e.g. cyclic boronates that display remarkable potency against β-lactamases ; such compounds have potential as transpeptidase inhibitors with very different PK/PD properties compared to classical β-lactams; (ii) Extensive new structural and mechanistic information on β-lactam mode of action and resistance mechanisms has emerged since the classical β-lactams were developed; (iv) New synthetic methodologies enable access to complex densely functionalised rings systems (e.g. functionalized oxapenems) previously unviable due to ‘cost of goods’ issues; (v) Knowledge of (Mtb infected) human cell biology will enable more rational targeting of β-lactams to Mtb in human cells. The focus of this OpenLab project will be structural, screening, and mechanistic work (including involving new inhibitors types) that will enable future medicinal chemistry efforts to enable clinically useful BlaC resistant PBP inhibitors for oral Mtb treatment.
EMBL- Unravelling new combinatorial therapies against Shigellosis (Europe)
Start : July 2018 | Status : Complete
The scientists: 2 FTE at EMBL
The sponsor: EMBL
Foundation funding: The Foundation is providing £131,383 in support
GSK’s contribution: GSK will provide expertise with high throughput screening set ups and compound screening, as well as with data analysis. GSK will provide compound libraries and drug discovery expertise to assist in the compound selection. Materials for the experimental part performed at GSK will be provided in kind. GSK pharmacologist experts will support this project to unravel the PK/PD of synergistic combinations.
Project Description:Combinatorial treatments provide an untapped, cost-effective source for new antibacterial treatments at a time where new therapies are urgently needed. Here we propose to establish a high-content microscopy platform for systematically screening drug combinations against intracellular Shigella. Shigellosis is one of the leading causes of diarrhea worldwide, with infections being more frequent and deadly in the developing world. The microscopy platform set up will not only facilitate high-throughput screening at the intracellular context of infection, where this pathogen has to be targeted, but will also provide insights into the mechanism-of-action of single drug(s) and the combinatorial treatment by monitoring the stage of infection and the host process(es) they affect. Using this platform, we will evaluate the impact of ~5,000 drug combinations during the course of infection in epithelial cells and macrophages. Strong synergies will be further evaluated in detailed surface response measurements (inhibition and killing curves – intracellularly and extracellularly), resistant and persistent assays. Last, prominent candidates will be moved to animal models and PK/PD measurements.
University of Washington - PK/PD modeling for anti-Shigella drug candidates (America)
Start : September 2017 | Status : Complete
The scientists: Dr. Samuel Arnold and Ms. McCloskey will focus their research on the setting up of an animal model of Shigella for assessing antibiotic efficacy and the integration of in vitro and in vivo data to generate a PBPK/PD model to enable the identification of novel anti-Shigella drug candidates. Samuel Arnold obtained his PhD in pharmaceutics from the University of Washington School of Pharmacy under the guidance of Dr. Nina Isoherranen. He has extensive background in pharmaceutical sciences including enzymology, pharmacology and clinical pharmacokinetics. He has recently contributed to the identification of gastrointestinal drug exposure as an important driver of anti-cryptosporidium drug efficacy.
Molly McCloskey graduated with a Bachelor of Science in Biology from Saint Vincent College, Latrobe, Pennsylvania. Since then, she has studied cellular architecture and the molecular components involved in single cell wound healing. She currently works in the Van Voorhis lab at the University of Washington, working on developing therapies for cryptosporidiosis and aiding in research of other infectious diseases.
The sponsor: University of Washington
Foundation funding: The Foundation is providing £199,874 in support
GSK’s contribution: GSK will contribute with its scientific expertise including DMPK support on lead drug candidates and access to PBPK/PD modeling resources.
Project Description:The project focuses on drug discovery for Shigella. Main challenges in development of anti-shigella drugs are the lack of suitable animal models to evaluate compounds and the lack of information on PK/PD to anticipate in vivo efficacy and human dose.
The first step in this project will be to test if the shigellosis B6 mouse model or other murine alternatives are suitable to evaluate antibiotics. Based on the localization of Shigella to the large intestine and the need to deliver antibiotics in GI tract, previous experience with PBPK-PD models to predict in vivo drug efficacy for anti-cryptosporidium drugs will be applied to predict in vivo efficacy of anti-Shigella compounds.
California Institute for Biomedical Research (America)
Start : November 2015 | Status : Complete
Foundation funding: The Foundation is providing £35,100 in support.
GSK’s contribution: GSK is providing expertise and know-how in high throughput screening and later compound profilling, as well as access to key facilities to set-up and perform this work. GSK is also providing information about the parasitological and toxicological profile of the promising molecules identified.
Project Description: Leishmaniasis and Chagas disease affect millions of people worldwide and impart a heavy burden on global health. Due to the limitations of the existing treatments, an urgent need exists to develop novel therapies to prevent and treat these diseases.
Phenotypic screening has proven to be an attractive screening approach to identify lead molecules against Leishmania and Chagas. Additionally, high-content imaging has allowed the development of novel assays to assess the therapeutic value of lead molecules against intracellular parasites in a format that better recapitulates the environment that parasites will encounter during the course of infection. Phenotypic screens employing intracellular amastigotes provides a privileged platform for screening novel libraries targeting either the parasite or the host cell. As part of the current project we intend to screen Calibr compound collection to identify novel hit-to-lead series for each parasite.
Caucaseco Scientific Research Center and Malaria Vaccine and Drug Development Center (America)
Start : September 2015 | Status : Complete
The scientists: Andres Amado will focus his research on the development of a platform dedicated to translate the malaria transmission blocking (TB) efficacy of anti-P. falciparum drugs to P. vivax. Andres is an entomological researcher at the Caucaseco Scientific Research Center (CSRC) and Malaria Vaccine and Drug Development Center (MVDC). He has experience working with malarial aspects of entomological field work, clinical trial studies and transmission blocking assays
The sponsors: Malaria Vaccine and Drug Development Center, Caucaseco Scientific Research Center.
Foundation funding: The Foundation is providing £46,466 in support.
GSK’s contribution: GSK will provide training to the OL scientist in terms of scientific expertise in performing mosquito based transmission blocking assays as well as provide access to a set of GSK compounds which have been demonstrated to have transmission blocking activity.
Project Description: Successful in vitro culture of all stages of Plasmodium falciparum gametocytes have led to the development of transmission blocking assays ranging from low to high throughput screens. The inability to successfully culture P. vivax in vitro impedes analogous efforts against P. vivax. For this reason we rely on Plasmodium vivax isolates from human patients / volunteers.
GSK DDW has recently established an Insectary facility with Anopheles stephensi mosquitoes, the main malaria mosquito vector from the Indo-Iranian region, with the goal of discovering anti-malarial molecules which block transmission of the sexual stages of the malaria parasite to the insect vector. Mosquito-based assays using in vitro grown P. falciparum gametocycte cultures have been standardized and are being used routinely to screen for anti-malarials with transmission blocking efficacy.
In this collaborative project a set of GSK compounds will be screened for activity against P. falciparum mature gametocytes in the Standard Membrane Feeding Assay (SMFA). The standard protocols developed at GSK for drug treatment of P. falciparum gametocytes, gametocyte viability and the SMFA will be adapted to the treatment of P. vivax gametocytes obtained from patient blood at the Caucaseco Scientific Research Center (CSRC) labs in Colombia. The same set of GSK compounds with P. falciparum transmission blocking activity will be used to treat P. vivax gametocytes which will be fed to An. albimanus mosquitoes in the Direct Membrane Feeding Assays (DMFA). Establishing such a platform dedicated to translation of efficacy of drugs from P. falciparum to P. vivax will greatly contribute to the discovery of molecules with P. vivax transmission blocking activity.
University of Dundee (Europe)
Start : September 2015 | Status : Complete
The scientist: Dr. Federica Prati will focus her research on the identification of novel leads for the TB target InhA via fragment-based drug discovery (FBDD) methods. Federica is Postdoctoral Researcher with the Drug Discovery Unit at the University of Dundee, working under the supervision of Prof. Paul Wyatt and Dr. Peter Ray. She is an organic/medicinal chemist by training, and her primary role in this project will be the design, synthesis, and optimisation of the compounds coming from fragment screening against the enzyme.
The sponsors: University of Dundee Drug Discovery Unit
Foundation funding: The Foundation is providing £133,740 in support, together with co-funding from the European Union FP7 program through its COFUND scheme.
GSK’s contribution: GSK will contribute in-kind with its extensive experience in InhA target-based programs for TB (J. Med. Chem. 2014, 57, 1276 – 1288; J. Med. Chem., 2015, 58 (2), pp 613–624). This experience will be leveraged not only in terms of inputting medicinal chemistry knowledge, but also in utilizing the existing InhA biochemical assay and crystallography platform.
Project Description: Isoniazid has been a staple of the TB drug regimen for more than 50 years. Because of this historical importance, its biological target, InhA, is one of the best validated enzymes for TB treatment. However, the increasing prevalence of isoniazid resistant forms of TB (along with other drug resistance issues), is threatening to become a major world health crisis if new drugs with efficacy against these resistant bacterial strains cannot be identified.
Critically, isoniazid resistance is primarily caused by mutations in the katG gene that encodes an enzyme that activates isoniazid to its active form. Therefore, compounds that directly inhibit InhA could be reasonably expected to recapitulate the clinical efficacy of isoniazid while maintaining activity against KatG mutants.
Previous efforts to develop direct InhA inhibitors, have generally struggled to identify compounds in optimal drug-like chemical space. By starting from very small, non-lipophilic hits, FBDD offers the opportunity to rationally design new inhibitors that are more likely to achieve the desired properties.
Martin Luther University of Halle (Europe)
Start : July 2015 | Status : Complete
The scientists: Dr Katja Laqua and Mr Henok Asfaw will focus their research on the discovery of new drugs for Tuberculosis disease, through a project entitled “Turning small potent antimycobacterial cyclo(depsi) peptides into drug-like scaffolds”. Dr. Katja Laqua has just finished her PhD at University Halle with Prof. Peter Imming. Her colleague, Mr Henok Asfaw Sahile, holds a Master Degree in Medicinal Chemistry, and he is a PhD student in Peter’s group. Both have extensive experience in organic synthesis and design of biologically active compounds
The sponsors:Martin Luther University Halle-Wittenberg – founded in 1502 – is an efficient, modern full-university, which maintains the highest academic requirements. At present, more than 21000 students are enrolled in the university, which encompasses over 190 courses of study in 18 faculties and departments. Its Institute of Pharmacy - part of the Biosciences Faculty – houses 13 professorships covering all aspects of drug-related research and teaching. Prof. Imming's department focusses on synthetic medicinal chemistry in the fields of antimycobacterial compounds and stable free radicals as ESR probes. His group also collaborates with a tuberculosis research institute and the university in Addis Ababa, Ethiopia.
Foundation funding: The Foundation is providing £ 154,794 in support.
GSK’s contribution: GSK will allocate in-kind contributions to the project, including scientific expertise in M.tuberculosis in vitro and in vivo assays, medicinal chemistry, DMPK and further profiling activities. GSK will provide access to the relevant facilities as well as the necessary laboratory supplies to carry out the different work packages.
Project Description: Although the Millennium Development Goal to halt and reverse the TB epidemic by 2015 has been achieved, the global burden of TB remains enormous. In 2012, there were 8.6M new cases of TB and 1.3M deaths. Additionally, MDR-TB cases were reported in all the countries surveyed by WHO. According to their estimates, there were roughly 500,000 new MDR-TB cases that year. As of March 2013, 84 countries had reported at least one XDR-TB case. Outcomes for these patients are depressingly poor.
Small peptides, cyclopeptides and cyclodepsipeptides have recently come to the forefront as potential antimycobacterial drug substances. At the Open Lab, Katja and Henok will be focused on the optimization of cyclodepsipeptides and related analogues that have shown good growth inhibitory against TB and no cytotoxicity, in order to turn active compounds of the peptide-type into drug-like molecules by means of combining activity and stability with suitable solubility and membrane permeability properties.
The duration of the project is 24 months and will involve a close collaboration between Martin Luther University Halle and GSK’s Medicines Development Campus at Tres Cantos.
Mahidol University (Asia)
Start : June 2015 | Status : Complete
The scientist: Dr. Krittikorn Kumpornsin will focus her research on the identification of new chemical entities efficacious against natural P. falciparum isolates from the patients with delayed parasitic clearance to artemisinin treatments through a project titled “Reversal of Artemisinin Resistance by means of Chemical Genetics”. Her work will contribute to tackle the emerging issue of decreased efficacy of current gold-standard antimalarial treatments, including artemisinin-combination therapies (ACTs). Krittikorn is a biochemist by training. She obtained her bachelor degree in Microbiology from Srinakharinwirot University (Thailand). She worked at the Division of Molecular Genetics, Siriraj Hospital and then at the department of Biochemistry, Mahidol University. Krittikorn obtained her Ph.D. in Biochemistry in 2014 from the University of Mahidol (Thailand) and has an extensive experience in malaria biochemistry and drug resistance.
The sponsors: Dr. Chookajorn’s laboratory at the Faculty of Tropical Medicine at Mahidol University based in Thailand is tackling the problems of malaria drug resistance and pathogenesis using molecular biology and evolutionary biology approaches. The drug resistance research they have conducted has been focused on the genetic interactions that affect the evolutionary course of gaining new resistant phenotypes. They take advantage of their privileged location in the drug-resistant hotspot of the Greater Mekong Subregion, which led in the past to their contributions to antifolate resistance evolution studies. Their location strategically allows direct access to field resources, such as patient isolates with a delayed response to current gold-standard antimalarial treatments (ACTs) and local experts.
Foundation funding: The Foundation is providing £84,212 in support.
GSK’s contribution: GSK will allocate in-kind contribution to the project, including extensive screening exercise and drug discovery mentoring. GSK will provide access to Biosafety Level 3 facilities to conduct in vitro malaria studies and to GSK´s collection of compounds for screening campaigns.
Project Description: Project Description: Artemisinin is an effective drug used for the treatment of Plasmodium falciparum malaria. The drug can quickly clear the parasites from the patients because of its broad activity against every stage within human red blood cells. Despite its effectiveness in saving lives, the target of artemisinin is not yet identified, preventing the possibility of exploiting a similar inhibitory mechanism for drug development. The lack of understanding has become a pressing issue now more than ever because of the rise in artemisinin resistance in Southeast Asia. It has been reported that certain oxidizing agents have the potential to moderately modulate the sensitivity level of artemisinin. This observation suggests the possibility that the effect of artemisinin on parasites could be manipulated by chemical compounds. The plan is to screen for compounds that can overcome artemisinin resistance, by “resensitizing” artemisinin-resistant parasites from patients with delayed clearance. The putative compounds are likely to interfere with the target of artemisinin or resistance mechanism. The innovation of the project proposal comes from the use of natural P.falciparum isolates from the patients with delayed parasite clearance by artemisinin that have been adapted for in vitro culture. These natural isolates provide a unique resource for screening purposes. The proposed duration of the project is 15 months and will involve a close collaboration between the University of Mahidol and GSK Medicine Development Campus at Tres Cantos.
Joan & Sanford Weill Medical College of Cornell University (America)
Start : March 2015 | Status : Complete
The scientist: Dr. Kaj Kreutzfeldt will focus her research on the discovery of new drugs for Tuberculosis (TB), through a project titled "Studies towards the identification of orally available beta-lactams with efficacy against Mycobacterium tuberculosis”. Kaj is a postdoctoral fellow at the Joan & Sanford Weill Medical College of Cornell University with Prof. Sabine Ehrt, and has extensive experience in host-pathogen interactions with a particular focus on mycobacterial infections and the resulting host immune responses.
The sponsor:Weill Cornell Medical College is among the top-ranked clinical and medical research centers in the US. The mission of the Medical College is to provide the finest education possible for medical students and students pursuing advanced degrees in the biomedical sciences, to enable them to conduct research at the cutting edge of knowledge and improve the health care of the nation and the world. Dr. Sabine Ehrt’s laboratory at Weill Cornell Medical College investigates the molecular mechanisms that allow Mycobacterium tuberculosis to establish and maintain persistent infections. Genetic strategies are applied to characterize host-pathogen interactions, identify proteins that help the pathogen resist eradication by the immune system and identify and validate new targets for TB chemotherapy.
Foundation funding: The Foundation is providing £139,032 in support.
GSK’s contribution: GSK is providing in-kind contributions, including scientific expertise for in vitro and in vivo characterization of Mycobacterium tuberculosis (Mtb), access to Biosafety Level 3 facilities and access to GSK´s compounds.
Project Description: TB remains a major public health threat and new drugs that shorten the current TB treatment regimen and cure both, drug sensitive and resistant TB, are needed to reduce the impact of this disease on global health. One of the most important classes of antibiotics for the treatment of bacterial infections are beta-lactam antibiotics, which also represent a major fraction of the global antibiotic market. However, beta-lactams have not been broadly used for treatment of TB, because Mtb produces a broad-spectrum beta-lactamase (BlaC) rendering it resistant to beta-lactams and the organism is protected by a relatively impermeable cell envelope. Nevertheless, the interest in beta-lactams for the treatment of Mtb infections has been renewed by the demonstration of irreversible inactivation of Mtb’s beta-lactamase BlaC by clavulanic acid. Additionally, a mounting body of anecdotal clinical evidence points towards a potential role of beta-lactams in combination therapy. Determining the efficacy of beta-lactams in a rodent animal model has been challenging. Hence,the ability to characterize orally available beta-lactams in a TB mouse model and the identification of compounds that synergize with orally available beta-lactams could have significant clinical implications.
The aim of this project is to utilize an Mtb mutant that is hypersusceptible to beta-lactams to (i) provide proof of concept that beta-lactams can be effective against Mtb in a mouse model, (ii) identify compounds that inhibit growth of intracellular Mtb by targeting proteins required for resistance to beta-lactams and (iii) identify compounds that could synergize with beta-lactams.
The proposed duration of the project is 24 months and will involve a close collaboration between Cornell University and GSK’s Medicines Development Campus at Tres Cantos.
Monash University (Oceania)
Start : March 2015 | Status : Complete
The scientist: Dr. Kevin Neildé will focus his research on the discovery of new drugs for Chagas disease, through a project titled "Hit to Lead Optimization for kinetoplastid diseases: single agents for Chagas”. Kevin is Postdoctoral Researcher at the Monash Institute of Pharmaceutical Science (Monash University, Australia) with Prof. Jonathan Baell, and has extensive experience in organic synthesis and design of biologically active compounds.
The sponsors: The Monash Institute of Pharmaceutical Science focus on medicinal chemistry for drug discovery. Research is both fundamentally focused – on chemistry and structure-based drug design – and translational. Working in a multidisciplinary, iterative feedback cycle of design, synthesis and biological testing, the objective is to optimise the potency, selectivity and bioavailability of a compound, while minimising side-effects. Monash´ research programs are undertaken with key industry partners, including biotechnology companies, large pharmaceutical companies and leading research institutions.
Foundation funding: The Foundation is providing £103,070 in support.
GSK’s contribution: GSK is providing in-kind contributions, including scientific expertise in T.cruzi in vitro assays, medicinal chemistry, DMPK and further profiling activities. GSK will provide access to the relevant facilities as well as the necessary laboratory supplies to carry out the different work packages.
Project Description: Trypanosoma cruzi is the causative agent of Chagas disease, which is spread by the bite of the assassin beetle (“kissing bug”) and endemic in 18 countries in Latin America. It is responsible for approximately 14,000 deaths and a disease burden of 0.7 million DALYs annually. It is also a primary cause of cardiomyopathy in the Americas. Two therapies are currently used for Chagas disease: nifurtimox and benznidazole. These drugs have adverse side-effects and they neither prevent the development of, nor can treat, chronic Chagas disease. There is a critical need for new treatment options for this neglected disease.
Researchers at Monash University, led by Pr. J.Baell, and University of Western Australia, led by Dr. Matthew Piggott, have recently identified compounds that show in vitro selective efficacy against T. cruzi and that have appropriate physico-chemical properties to be further progressed. In the frame of this project, two chemical series will be fully profiled and SAR studies established to optimize the hit compounds reach a good in vivo activity and fulfill the criteria for further development into lead compounds.
Harvard Medical School (America)
Start : January 2015 | Status : Complete
The scientists: Dr. Hugo Fraga is a PhD Research Associate at Harvard Medical School working in Dr. Goldberg´s lab in the Cell Biology department. He has extensive experience researching the structure of ClpP, including recently in Grenoble, France. Annie Park is a graduate student in the Biological and Biomedical Sciences program at Harvard’s Graduate school of Arts and Sciences.
The sponsors: Harvard Medical School has been synonymous with excellence in education and research for generations. Dr. Alfred Goldberg has been associated with Harvard during his entire academic career and is currently professor of Cell Biology. His lab has long been a leading center for studies of the regulation and mechanisms of protein breakdown in animal and bacterial cells.
Foundation funding: The Foundation is providing £ 238,110 in support.
GSK’s contribution: GSK is providing in-kind contributions including access to the GSK´s collection of compounds, scientific expertise in HTS enzymatic campaigns and antitubercular characterization capacity of the hits identified.
Project Description: The project objective is the screening for inhibitors of the function or formation of the ClpC1P1P2 complex from M. tuberculosis (M.tb). The blocking of ClpP1 or ClpP2 function or its regulatory ATPases, ClpX, and ClpC, rapidly kills growing and non-growing M.tb. Recently, two novel cyclic peptide antibiotics (lassomycin and ecumicin) were shown to selectively kill M.tb by activating ClpC1 ATPase, uncoupling ATP hydrolysis from protein degradation and thus preventing the regulated, breakdown of cell proteins. These findings provide strong validation for these targets and the rationale for this project.
The project team will screen for small molecules that block ATP-dependent degradation of a fluorescent protein substrate by the ClpC1P1P2 complex. This assay will screen for inhibitors of ClpP1P2 activity, its association with ClpC, as well as ClpC’s multiple functions (ATPase unfolding, protease activation). For confirmed hits, we shall determine which component of the ClpC1P1P2 complex is affected. Possible effects on the ClpP1P2 proteolytic activity will be tested using isolated ClpP1P2 and a sensitive fluorescent substrate. Effects on ClpC will be tested by assaying ATP hydrolysis. Disruption of the interaction between the ATPase and protease would result in blockage of protein degradation without effects on peptide or ATP hydrolysis.
CIDR / Seattle Biomed Research Institute (America)
Start : January 2015 | Status : Complete
The scientist: Anke Harupa is a postdoctoral fellow who will focus her research on the discovery of new drugs against malaria through a project titled "Identification of small-molecule inhibitors of Plasmodium NMT”. The project is led by Dr. Alexis Kaushansky, Senior Scientist in the group of Dr. Stefan Kappe at Seattle Biomedical Research Institute. Anke has more than four years of experience in malaria research working in the group of Dr. Kappe, and has numerous publications of scientific relevance.
The sponsor: Seattle Biomedical Research Institute has one of the largest malaria research programs in the United States with a particular focus on molecular biology aspects of the most virulent malaria parasite Plasmodium falciparum, in addition to vaccine discovery efforts focusing on malaria in pregnancy, severe malaria in children and liver-stage malaria.
Foundation funding: The Foundation is providing £ 145,027 in support, together with co-funding from the European Union FP7 program through its COFUND scheme.
GSK’s contribution: GSK is providing in-kind contributions, including scientific expertise in malaria from supporting scientist in screening, enzymology, medicinal chemistry, in vitro-ex vivo parasite expertise, access to Biosafety Level 3 facilities and to GSK´s collection of proprietary compounds.
Project Description: The Plasmodium parasite has a complex lifecycle that alternates between extracellular invasive stages and intracellular replicative stages in two hosts, mosquito and man. Once transmitted by a mosquito, the sporozoite form of the parasite infects the liver and generates thousands of merozoites which invade red blood cells, multiply inside them, and egress to infect new red blood cells. Some merozoites develop into gametocytes which are ingested by a mosquito, where they fertilize and eventually produce sporozoites, which completes the lifecycle. The asexual intra-erythrocytic stages are responsible for all clinical symptoms of malaria and are therefore the main focus of drug research. Ideally, novel drugs should target multiple stages of the parasite’s lifecycle to not only treat but also prevent disease and transmission. The enzyme N-myristoyltransferase (NMT) is a potential multi-stage antimalarial drug target as it is expressed throughout the parasite lifecycle. NMT is not unique to Plasmodium but is present in all eukaryotic organisms. It catalyzes the attachment of a myristate to certain substrate proteins, which is important for protein stability and protein association with membranes. A gene-knockout study in P. falciparum suggests that NMT is essential in asexual blood stages, and NMT has been recently validated as a drug target in these stages. Inhibition of NMT resulted in non-infectious parasites, in parts due to the failure to assemble the inner membrane complex, which is a critical structural component for parasite motility and host cell invasion. The objective of our project is to perform a screening of compound libraries to identify selective Plasmodium NMT inhibitors and test their effect on the different lifecycle stages of the parasite with a focus on the parasite’s motility and cell invasion capacities.
The University of British Columbia (America)
Start : October 2014 | Status : Complete
The scientist: Dr. Santiago Ramón-García is a Research Associate in Charles Thompson’s lab (Department of Microbiology & Immunology and the Center for Tuberculosis Research) at the University of British Columbia (UBC), Canada. At UBC, Santiago has developed a new screening approach for tuberculosis (TB) drug discovery based on the identification of synergistic combinations of drugs already approved for clinical use.
The sponsor: The University of British Columbia (UBC), established in 1908, is one of the top leading research universities in Canada and worldwide. TB research at UBC expands from basic to translational projects aiming to understand both the molecular mechanism of antibiotic resistance and infection used by Mycobacterium tuberculosis, the causative bacterial agent of TB, and to develop novel TB therapeutics.
Foundation funding: The Foundation is providing £ 170,240 in support, together with co-funding from the European Union FP7 program through its COFUND scheme.
GSK’s contribution: GSK is providing expertise and in-kind contributions in High Throughput Assays (HTA), in vitro pharmacokinetic and pharmacodynamic (PK/PD) modeling, and pre-clinical in vivo TB models. GSK is also providing access to Biosafety Level 3 facilities and GSK’s collection of compounds.
Project Description: One approach to generate new TB treatment options in a timely and cost-effective manner is “repurposing” clinically used drugs with known pharmacokinetic and safety data; thus allowing for rapid evaluation in clinical trials. In addition, drug repurposing is a strategy that would allow for an easier long-term implementation since manufacturing and distribution infrastructure is already established.
Rifampin (RIF) is a cornerstone drug in TB therapy, having both bactericidal and sterilizing activity. Numerous in vitro, in vivo and clinical investigations suggest that there is a direct relation between RIF dose increase and efficacy, but use of higher doses is limited by the toxicity profile. Thus, if higher efficacy could be achieved for a given dose of RIF by augmenting it’s anti-tuberculosis activity TB therapy could be potentially shortened, reducing the rate of TB transmission, and the development of resistant strains
At UBC, Dr. Ramón-García identified conventional antibiotics that enhance RIF’s in vitro activity. His work at GSK will further explore the synergistic drug interactions of RIF using GSK’s collection of compounds. Santiago will pre-clinically develop those compounds originally identified at UBC in addition to new leads generated at GSK.
University of Sydney (Oceania)
Start : August 2014 | Status : Complete
The scientist: Dr Jessica Baiget will focus the research on the discovery of new drugs for Mycobacterium tuberculosis infection through a project titled "An Open Source Hit-to-Lead Campaign in Tuberculosis Drug Discovery”. Jessica is an experienced researcher who will drive this project under guidance of Associate Professor Matthew Todd, currently involved with the Australian Research Council/MMV-funded Open Source Malaria project, which involves hit-to-lead and lead optimization campaigns in the public domain.
The sponsors: The University of Sydney, founded in 1850, is Australia’s first university and has built a solid international reputation for itself over the past 150 years. It is considered one of Australia’s leading educational institutions, playing a key role as a member of both the Group of Eight and the Association of Pacific Rim Universities (APRU).
Foundation funding: The Foundation is providing £68,916 in support.
GSK’s contribution: GSK is providing in-kind contributions including biological evaluation, facilities and expertise from supporting scientists.
Project Description: Mycobacterium tuberculosis (TB) is a human pathogen that infects up to one-third of the global population and causes one of the most recalcitrant bacterial infections of the modern era. Current drug discovery efforts toward TB are significant, but are taking place in a challenging environment. Collaborations to improve research efficiency are frequently limited, preventing those with high levels of expertise from participating. Many research projects do not share negative data, preventing the formation of an effective scientific model. Many existing chemical compounds worldwide are not evaluated in medicinal chemistry campaigns because the owners of those compounds are unaware of the compounds’ potential.
This project employs a fully open source approach using public domain GSK compounds active against TB as the starting point. All data and ideas are freely shared. A TB hit-to-lead campaign will be pursued, with the intention of developing sufficient preliminary data for major future grant funding beyond the Tres Cantos Open Lab Foundation award. Associate Professor Todd recently demonstrated the idea of open source science in the synthesis of the anthelmintic praziquantel as a single enantiomer. More recently he has applied the same ideas in drug discovery with the Medicines for Malaria Venture founding the Open Source Malaria consortium. More than 200 new public domain compounds have been synthesized and nanomolar hits have been evaluated in vivo. The open nature of the project has stimulated intellectual and practical contributions from scientists outside the core team. This state of the art will be combined with GSK’s open TB data to develop an open source project in TB, but with additional components that will overcome limitations of the open source model identified to date, such as the ability to acquire archived compounds not listed in commercial or academic databases.
Universidad San Pablo CEU and University of Glasgow (Europe)
Start : July 2014 | Status : Complete
The scientist: Dr Emily Grace Armitage will focus her research on the discovery of new drugs for Leishmania donovani disease, through a project titled "Use of metabolomics to determine modes of action of novel anti-leishmanial compounds”. Emily is Postdoctoral Researcher at the Center of Excellence of Metabolomics and Bioanalysis (CEMBIO) in the Universidad San Pablo CEU with Prof. Coral Barbas, and has extensive experience in the metabolomic field where she has numerous publications of scientific relevance.
The sponsors: Universidad San Pablo – CEU (USP-CEU) and the University of Glasgow (UoG) house state of the art metabolomics platforms and have pioneered studies into the metabolomics of parasitic protozoa. The combination of metabolomic platforms offered at USP-CEU provides complementary information covering a large proportion of the metabolome. UoG houses the Scottish Metabolomics facility and has established a platform based on Fourier transform mass spectrometry coupled to liquid chromatography (as well as Gas chromatography–mass spectrometry, GC-MS, and Nuclear magnetic resonance, NMR). Bringing together these two centres offers an exciting opportunity to accelerate the implementation of metabolomics as a routine part of the drug target evaluation pathway. The UoG centre has pioneered studies demonstrating that metabolomics can identify targets of anti-protozoal drugs. USP-CEU have already demonstrated how their platform can identify changes in leishmania with resistance to antimonials and the mechanism of action of miltefosine in both wild and resistant parasites
Foundation funding: The Foundation is providing £150,055 in support.
GSK’s contribution: GSK is providing in-kind contributions, including scientific expertise in leishmania to obtain the extracts from in vitro parasite culture, and access to Biosafety Level 3 facilities and to GSK´s collection of compounds.
Project Description: Screening of compound libraries for potential new antimicrobial agents has demonstrated the superiority of whole organism (phenotypic) screening to identify hits for further development. Such screens require compounds to already demonstrate key pharmacological criteria required for parasite killing, including an ability to enter cells and find targets in situ. However, phenotypic screens are hampered by the fact that drug targets are not known. This can hinder our ability to progress from hit to lead to drug, where target knowledge can guide medicinal chemistry in improving efficacy. In recent years metabolomics has been applied to drug target discovery and also to identify resistance mechanisms. This project aims to use metabolomics to identify modes of action of new compounds identified by phenotypic screening against Leishmania. Hits from the GSK anti-Leishmania screening campaign will be analysed firstly to allow clustering of drugs according to how they alter the metabolome and then focusing on a limited set of representatives to identify individual drug targets. The proposed duration of the project is 18 months and will involve a close collaboration between the Universidad San Pablo CEU, the University of Glasgow and GSK’s Medicines Development Campus at Tres Cantos.
Medical Research Council (Europe)
Start : May 2014 | Status : Complete
The scientist: Dr Ana Sánchez Azqueta is focusing her research on the discovery of new drugs against malaria through a project titled ‘Screening and identification of anti-malarial compounds that act via the inhibition of the PfCLK family of protein kinases’. Ana is a postdoctoral researcher in Prof. Andrew Tobin’s group at the MRC’s Toxicology Unit in Leicester. Her area of expertise is protein-ligand interactions and enzyme kinetics.
The sponsor: The UK’s Medical Research Council has been at the forefront of scientific discovery to improve human health. Founded in 1913, the MRC currently invests UK taxpayers’ money into some of the best medical research in the world across every area of health. The laboratory of Prof. Andrew Tobin has developed expertise in the role of protein phosphorylation in maintaining essential processes in P. falciparum. The laboratory has received an MRC Developmental Gap Fund (DGF) Award to co-fund the Open Lab collaboration. The MRC DGF Award exists to bridge the translational gap between MRC scientists’ basic research and the next translational milestone on the way to patient benefit.
Foundation funding: The Foundation is providing £14,500 in support.
GSK’s contribution: GSK is providing in-kind contributions, including expertise, facilities and consumables to develop and perform the HTS, access to compound collection (TCAMS), early in vitro toxicology and in vitro ADME studies as well as drug discovery expertise for hit prioritisation once the HTS campaign has been completed.
Project Description: This project will address whether protein kinase inhibitors specific against the PfCLK kinases can be developed as a safe and curative treatment for malaria. Furthermore, this project will also contribute to the question of whether protein kinase inhibitors can be used to target malaria beyond the blood stage. This project will specifically address the following problems:
- To define selective inhibitors to the PfCLK family
- To determine the anti-malarial activity of PfCLK the inhibitors (in vitro and in vivo) and establish the mode of action of the inhibitors
The duration of the project is expected to be 12 months and will involve a close collaboration between the MRC’s Toxicology Unit and scientists at GSK’s Tres Cantos Medicines Development Campus.
Weill Cornell Medical College (America)
Start : April 2014 | Status : Complete
The scientists: Dr. Shipra Grover is an experienced microbiologist who completed her doctoral studies in University of Birmingham (UK) under the supervision of Dr. Gurdyal Besra. Shipra has focused her research on uncovering the mode of action of new antituberculars and the transcriptional regulation of genes involved in cell wall biosynthesis.
The sponsor: Dr. Schnappinger´s laboratory at Weill Cornell Medical College pioneered the development of regulated expression systems for mycobacteria and showed how these systems can conditionally silence Mtb genes during mouse infections. The application of these novel technologies to drug discovery has allowed the (i) functional classification of Mtb growth inhibitors, and (ii) the application of novel target-biased whole cell screening anti-mycobacterial programs.
Foundation funding: £135,250
GSK’s contribution: GSK is providing in-kind contributions including access to BSL3 facilities, HTS and microbiology expertise as well as full access to antimycobacterial compounds sets.
Project Description: Whole-cell screens (WCS) have recently been re-visited as an antibacterial drug discovery strategy. This change is due to the lack of success associated with biochemical target-based high throughput screens (HTS), where potent enzyme inhibitors poorly active as antibacterials were identified. However, the ability to select for whole-cell activity during the HTS phase comes at the price of knowing little (if anything) about the mechanism(s) by which a novel compound inhibits bacterial growth. The use of regulated expression sytems can help overcome this shortcoming and identify the molecular target(s) of growth-inhibiting small molecules
The mode of action elucidation of GSK antitubercular compound sets by means of the conditional mutants developed by Dirk Schnappinger´s group at Cornell will be the base of this new whole cell target-based project.
Harvard School of Public Health and Broad Institute (America)
Start : April 2014 | Status : Complete
The scientists: This project is run by Dr. Leila Ross, an experienced parasitologist from the Department of Immunology and Infectious Diseases led by Dyann Wirth at the University of Harvard. Leila will focus her research on identifying and developing partner drugs for pyrimidine biosynthesis inhibitors that suppress the development of resistance in Plasmodium falciparum.
The sponsor: The Wirth laboratory blends the scientific environments of the Harvard School of Public Health, the Broad Institute, and collaborators from around the globe to create a unique malaria research and training network that brings together scientists with expertise in molecular biology, genetics, genomics, population genetics, chemistry, cell biology, epidemiology, computational biology, and biostatistics with leading clinicians in infectious diseases and pathology. The group has applied state of the art technologies and novel approaches to better understand the fundamental biology of the malaria parasite and mechanisms of drug resistance. The group has been one of the international leaders in technology development for Plasmodium falciparum genotyping and has helped identify over 112,000 genetic singlenucleotide polymorphisms (SNPs) across the P. falciparum genome.
Foundation funding: The Foundation is providing £9,948 in support.
GSK’s contribution: GSK is providing in-kind contributions including facilities and expertise from supporting scientists in Biochemistry, Screening and Medicinal Chemistry for DHODH inhibitors, and also through access to GSK´s collection of compounds.
Project Description: Drug resistance is reported for nearly every anti-malarial in use. The resistance can be suppressed with a population biology trap: by identifying situations where resistance to one compound confers hypersensitivity to another, combination therapies can be designed that not only kill the parasite, but also guide its evolution away from resistance.
This concept, termed “targeting resistance,” was applied to the malaria enzyme dihydroorotate dehydrogenase (PfDHODH). PfDHODH catalyzes the rate-limiting step in pyrimidine biosynthesis and has been well-validated as an anti-malarial target. In vitro resistance selections with PfDHODH inhibitors led to point mutations in PfDHODH. Characterization of these resistant parasites showed that resistance to one PfDHODH inhibitor did not give cross-resistance to all others; in fact, these strains were now hypersensitive to several other structural classes of inhibitors. Pairing different PfDHODH inhibitor classes largely suppressed the emergence of resistant parasites over 35 generations, which is enough time to mutate every nucleotide in the genome in the population size used.
To further develop this project, the focus will be on the identification of inhibitors of mutant PfDHODH with no residual activity against the wild-type. Novel inhibitors will be employed in studies of the enzymology of DHODH and used in further resistance selection experiments and fitness cost studies.
University of Glasgow (UoG), Marine Biological Laboratory (MBL) and Northeastern University (NEU) (Europe, America)
Start : January 2014 | Status : Complete
The scientists: Sofia Olego, a postdoctoral fellow working in the research group led by Prof. Harry De Koning, is joining the Tres Cantos Open lab to perform a focused screening to identify new small molecules active against Trypanosoma brucei via modulation of trypanosomal cAMP signaling, including phosphodiesterases (PDEs). Following identification of the hits, efforts will shift to NEU, UoG, and MBL for optimization follow-up work and assessment of hit chemotypes in cAMP signaling in trypanosomes and in TbrPDEB assays. This work will also be supported by a postdoctoral chemist who will join the project in July 2014.
The sponsor: The University of Glasgow (UoG) founded in 1451 is the fourth oldest university in the English-speaking world. Today they are a broad-based, research intensive institution with a global reach. The Institute of Infection, Immunity and Inflammation comprises scientists and clinicians working together to promote and develop research, drug discovery and ultimately improvements in patient care in this area of critical international importance. The Marine Biological Laboratory (MBL) is an international center dedicated to scientific discovery and improving the human condition through research and education in biology, biomedicine, and environmental science. Founded in Woods Hole, Massachusetts, in 1888, the MBL is a private, nonprofit institution and an affiliate of the University of Chicago. Northeastern University (NEU) founded in 1898 is a global, experiential, research university built on a tradition of engagement with the world, creating a distinctive approach to education and research. They pursue solutions to global health challenges across a broad front, from developing nanotechnology-based cancer therapies and synthesizing new biopharmaceuticals, to identifying ways to make the health-care system more efficient and more equitable.
Foundation funding: The Foundation is providing £123,602 in support.
GSK’s contribution: GSK is providing in-kind contributions (including facilities and expertise from supporting scientists for HTS, Medicinal Chemistry and GSK collection of compounds).
Project Description: The project is a collaboration of three academic partners, with Prof. De Koning (UoG) providing biochemical Parasitology, Prof. Michael Pollastri (NEU) providing Medicinal Chemistry and Dr Robert Campbell (MBL) providing protein chemistry and pharmacological expertise. The goal of this three-way collaboration is to identify advanced PDE inhibitors with appropriate properties for new HAT therapeutics.
Human African trypanosomiasis (HAT), better known as sleeping sickness, is caused by subspecies of the eukaryotic protozoan parasite T. brucei and affects at least 10,000 patients annually.(1) Established therapies have severe safety and efficacy limitations and, since the most debilitating and lethal condition occurs after the parasite has penetrated the CNS from the peripheral circulation, drugs must also pass into the brain.
Elucidation of the T brucei genome has enabled discovery of essential targets in this pathogen. Some of these are homologous to human proteins that have been aggressively pursued by the pharmaceutical industry, leading to the generation of huge estates of medicinal chemistry knowledge and drug-like chemical matter. One such target family is the PDEs, of importance in multiple indications in humans. Two essential PDEs have been identified in T brucei (TbrPDEB1 and B2). The inhibition of these targets elevates cAMP levels in trypanosomes, leading to cell death. (2)
Two research teams have been working on optimization of inhibitors of TbrPDEB1 and B2 over the last several years: The Pollastri and Campbell Laboratories (NEU and MBL, respectively), and a consortium of researchers based mostly in the Netherlands (“TIPharma”). Much of the fundamental work for the rigorous pharmacological validation of TbrPDEs and the characterization of the cellular effects of PDE inhibition has been performed in the De Koning lab at UoG.
This project will explore the GSK chemotype space for HAT, leveraging extensive experience and data within the company, to identify new, CNS-penetrant compounds that display potent activity against human-infective trypanosomes, selectivity over human PDEs and that operate via cAMP-modulating pathways (including, but not limited to, TbrPDEs).
(1) Savioli, L.; Daumerle, D. Sustaining the drive to overcome the global impact of neglected tropical diseases. Published Online: 2013. http://apps.who.int/iris/bitstream/10665/77950/1/9789241564540_eng.pdf.
(2) De Koning HP, Gould MK, Sterk GJ, Tenor H, Kunz S, Luginbuehl E, and Seebeck T (2012) Pharmacological validation of Trypanosoma brucei phosphodiesterases as novel drug targets. J Infect Dis 206:229-237; Bland, N. D.; Wang, C.; Tallman, C.; Gustafson, A. E.; Wang, Z.; Ashton, T. D.; Ochiana, S. O.; McAllister, G.; Cotter, K.; Fang, A. P.; Gechijian, G.; Garceau, N.; Gangurde, R.; Ortenberg, R.; Ondrechen, M. J.; Campbell, R. K.; Pollastri, M. P. Pharmacological validation of Trypanosoma brucei Phosphodiesterases B1 and B2 as druggable targets for African sleeping sickness. J. Med. Chem. 2011, 54, 8188-8194
Start : January 2014 | Status : Complete
The scientists and the sponsor: This project is led by Dr. Simon J. Teague, assisted by Dr. Ian Millichip. The collaboration between TeagueMedChem Ltd and GSK results from world-wide crowdsourcing for new ideas concerning tuberculosis treatment through http://www.innocentive.com. Competitive examination of more than one hundred proposals resulted in selection of this project.
Foundation funding: The Foundation is providing £93,587 in support.
GSK’s contribution: GlaxoSmithKline is providing in-kind contributions including biological evaluation, facilities and expertise from supporting scientists.
Project Description: The project focuses on drug discovery for tuberculosis and is titled “New medicines for tuberculosis through Rifamycin semi-synthesis.” Rifamycin has been the mainstay of tuberculosis combination therapy for more than forty years.
Many antibacterial agents are only bacteriostatic, but Rifamycins are bactericidal. They kill the “persister” bacteria which cause relapse once therapy is stopped and are a key component of DOTS combination therapy. The current limitations of the Rifamycins are Cyp induction, solubility and resistance. Cyp induction results in clinically significant drug-drug interactions, especially for patients who are HIV co-morbid. Almost all known Rifamycin analogues are produced by derivatization of just two positions of the natural product. This derivatization is constrained by synthetic considerations leading to exploration of a very restricted activity and property space. In this project, Rifamycins are subjected to semi-synthesis rather than derivatization. The macrocycle is cleaved in half and entirely new replacements for the naphthoquinone moiety inserted producing novel macrocycles. This may allow for the production of entirely new, designed Rifamycin-like compounds with improved properties and modified resistance profile. The ways in which Rifamycins work has been exhaustively studied over many years. This project attempts to apply this accumulated understanding in the design of new medicines which are useful for treating tuberculosis.
SUNY Upstate Medical University (America)
Start : October 2013 | Status : Complete
The scientists: Dr. Kristina Wickham, a postdoctoral researcher working on the research team led by Professor Rosemary Rochford, at SUNY Upstate Medical University has joined the Tres Cantos Open Lab to progress a project which aims to develop a liver stage mouse model for Plasmodium falciparum. Rosemary Rochford, the Vice President for Research at SUNY Upstate and Professor of Microbiology and Immunology, is a noted expert in the field of endemic Burkitt's lymphoma (eBL) and the role Epstein-Barr virus and co-factors including holoendemic malaria have in the emergence of eBL. The Rochford lab has developed and validated a humanized SCID (severe combined immunodeficiency) model to test the hemolytic toxicity of anti-malarial drugs in mice engrafted with glucose-6-phosphate deficient human red blood cells, which is supported with funding from the Medicines for Malaria Venture and the U.S. Department of Defense.
The sponsor: With the distinction of being the only academic medical center in Central New York, the core mission of SUNY Upstate Medical University is to improve the health of the community through education, biomedical research and health care. Upstate Medical University's educational mission is anchored by its four colleges — Medicine, Nursing, Health Professions and Graduate Studies (biomedical sciences). As a biomedical research enterprise, Upstate focuses on the most prevalent human diseases including cancer, diabetes, heart disease, nervous system disorders, vision, and infectious diseases. The quest for treatments and cures is built upon expertise in structural, molecular and systems biology. Upstate also offers many clinical trials for patients. The Upstate University Health System serves 1.8 million people, often the most seriously ill and injured, and includes Upstate University Hospital; Upstate University Hospital at Community Campus; Upstate Golisano Children's Hospital, and numerous satellite sites.
Foundation funding: The Foundation is providing £ 59,333 in support of this research.
GSK’s contribution: GSK is providing in-kind contribution including access to the insectary with Plasmodium falciparum-infected mosquitoes and Biosafety Level 3 facilities, and staff support and expertise in humanized mouse models for malaria.
Project Description: P. falciparum is the deadliest of the five parasite species that cause malaria in humans. A striking limitation of current malaria research is the lack of adequate preclinical animal models that can directly support the exoerythrocytic phase of P. falciparum infection. This impedes the further understanding of Plasmodium biology as well as development and interrogation of antimalarial drugs. Previous work by the Rochford lab has demonstrated that tumors retaining hepatocyte-like characteristics can be established in NOD (non-obese diabetic)/SCID mice with minimal technical manipulation, circumventing significant challenges encountered by other humanized mouse models for P. falciparum liver stage infection.
During her time in the Open Lab, Kristina will investigate the capability of these “pseudo-livers” to reproduce a biologically relevant P. falciparum infection. This pseudo-liver model would significantly advance the capacity to directly test the efficacy of antimalarial compounds in the context of human liver stage P. falciparum infection.
University of British Columbia (America)
Start : July 2013 | Status : Complete
The scientists: Flavia Sorrentino, a postdoctoral fellow working in the research group led by Prof. Yossef Av-Gay, is joining Tres Cantos Open lab to perform a high-throughput screening to identify new small molecules that enable eradication of Mycobacterium tuberculosis that infects immune cells present in our lungs that are called macrophages. Prof. Av-Gay’s laboratory research is focused on the studying biochemical and physiological processes of M. tuberculosis and its interactions with the human host in order to identify new targets for drug therapy.
The sponsor: The University of British Columbia (UBC), established in 1908, is one of Canada’s leading research universities. The Division of Infectious Diseases in the UBC Department of Medicine is actively involved in combating infectious diseases through patient care, education, and research.
Foundation funding: The Foundation is providing £139,750 in support.
GSK’s contribution: GlaxoSmithKline is providing expertise in High Content Imaging Assays, Biosafety Level 3 facilities and access to the GSK collection of compounds.
Project Description: M. tuberculosis is an obligate intracellular parasite whose success as a pathogen relies on its ability to evade the human immune system by residing and replicating inside macrophages. Data from the Av-Gay lab and others showed that Mtb targets host-signaling pathways to block the macrophage “normal” killing machinery, which is aimed at the isolation and destruction of invading microorganisms. While at the Open Lab, Flavia will perform a new high throughput screening aimed at identifying compounds that could enhance the macrophage ability to kill Mtb. This approach will utilize human macrophages, the “natural” host for Mtb, making this assay more likely to identify disease relevant inhibitors.
Center for Tropical and Emerging Global Diseases, University of Georgia (America)
Start : June 2013 | Status : Complete
The scientists: This project is run by Dr Rosa Suarez and Dr Mariano Tilve. The project focuses on the discovery of new drugs for Chagas disease and is titled “Development of anti-T. cruzi drugs targeting fatty acid utilization” . Rosa and Mariano are experienced chemists from the Tarleton Research Group led by Prof. Rick L. Tarleton leads at the University of Georgia.
The sponsor: The Center for Tropical and Emerging Global Diseases (CTEGD) at the University of Georgia is a university-wide, interdisciplinary center established in 1998 to foster research, education and service related to tropical and emerging infectious diseases. Based on a strong foundation of parasitology, immunology, cellular and molecular biology, biochemistry and genetics, CTEGD is made up of a wide range of research programs that focus largely on protozoan and metazoan parasites, their hosts and their vectors. Many of these programs have major international, on-site components for both research and training, where the faculty and trainees deal with these global infections and the populations that harbor them. CTEGD's investigators and their laboratories have made major contributions to our understanding of the diseases they study, such as malaria, Chagas disease, toxoplasmosis, cryptosporidiosis, lymphatic filariasis, African sleeping sickness, leishmaniasis and schistosomiasis -diseases of poverty that contribute enormously to global death and disability.
Foundation funding: The Foundation is providing £121,272 in support.
GSK’s contribution: GlaxoSmithKline is providing in-kind contributions (including facilities and expertise from supporting scientists for Medicinal Chemistry and also through access to GSK´s collection of compounds).
Project Description: There are no vaccines to prevent T. cruzi infection and the current available chemotherapies - benznidazole and nifurtimox - require long courses of treatment and exhibit variable efficacy. Although this infection is generally well-controlled by host immune responses, with relatively low incidence of severe or life-threatening acute infections, the long-term persistence of T. cruzi results in >30% of infected subjects developing severe and eventually fatal heart disease later in life. This project will focus on the discovery of more potent and parasite-selective compounds that attack the T. cruzi infection at the main point of its pathogenesis – its ability to persist for decades in muscle and adipose tissues. The project will comprise screening using in vitro tests, a short-term in vivo screening assay, and (for highly selected compounds) a test of cure in mice. Selected drug candidates will be less toxic and more potent compared to those of current chemotherapies.
University Of Helsinki (Europe)
Start : May 2013 | Status : Complete
The scientists: With the emergence of strains of Plasmodium falciparum that are developing resistance against the currently most effective antimalarial drugs, a new class of antimalarials is urgently required. At the Open Lab, Leena Keurulainen and Mikko Vahermo, doctoral researchers working in a group headed by Dr. Jari Yli-Kauhaluoma, Professor and Head of the Pharmaceutical Chemistry Division and jointly supervised by Dr. Paula Kiuru, a post-doctoral researcher at the University of Helsinki are focusing their research to try to identify and synthesize an antimalarial lead compound with a benzimidazole core.
The sponsor: The University of Helsinki was founded in 1640. It is one of the best multidisciplinary research universities in the world. The high-quality research creates new knowledge for educating specialists in various fields as well as for utilisation in social decision-making and the business sector. The University of Helsinki is an active, international academic community of 40,000 students and staff members. It operates on four campuses in Helsinki and at 17 other locations.
Foundation funding: The Foundation is providing £135,240 in support of this research.
GSK’s contribution: GSK is providing in-kind contributions (including facilities and expertise from supporting scientists for HTS and access to the compounds library).
Project Description: Leena and Mikko are using a benzimidazoIe derivative synthesized at the University of Helsinki which has shown activity against protozoan parasites. Following this discovery, Leena and Mikko conducted a structure search of the Tres Cantos Antimalarial Set (TCAMS) which led to the identification of some structural analogues which are endowed with antiplasmodial properties. At the Open Lab, Leena and Mikko are focusing on the optimization of this series with the ultimate objective of finding a lead with good therapeutic efficacy in the mouse model of Plasmodium falciparum infection that could eventually be further developed.
GSK´s expertise in biological testing and ADMET will greatly improve the speed of the development cycles and this in turn gives our project a bigger chance of being successful. (Leena Keurulainen, Open Lab Scientist)
Weill Cornell Medical College (America)
Start : May 2013 | Status : Complete
The scientists: Dr. Saki Raheem, a postdoctoral researcher working in a team led by Prof Kyu Y Rhee. Prof Rhee is an infectious disease expert who is an Associate Professor of Medicine in the Division of Infectious Diseases and Associate Professor of Microbiology and Immunology. Dr. Raheem will be responsible for conducting this research at Tres Cantos.
The sponsor: Located in New York City, Weill Cornell Medical College is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson’s disease, and most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with New York-Presbyterian Hospital, where its faculty provides comprehensive patient care at New York-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston.
Foundation funding: The Foundation is providing £145,000 in support of this research.
GSK’s contribution: GSK is providing in-kind contributions (including facilities and expertise from supporting scientists for HTS and access to the compounds library).
Project Description: Despite major advances in high-throughput screening and genomic technologies, TB drug development remains hindered by a general inability to measure the penetration of a given compound into Mycobacterium tuberculosis (Mtb). Over the past years researchers at Weill Cornell Medical College have developed a set of analytical methods and tools capable of capturing and enumerating the intracellular small molecule inventory of Mtb (metabolome). Utilization of this platform to monitor intracellular accumulation of current drugs has revealed an unexpected dissociation between cell permeability and anti-mycobacterial activity.
Access to GSK’s chemical library will allow us to screen different classes of compounds against TB, using metabolomics technology developed by Weill Cornell Medical College. As a result, we will create a centralized data repository of mycobacterial permeability data that will contribute to development of next generation of anti-TB drugs and fundamental knowledge of Mtb metabolomics. (Dr. Saki Raheem, Open Lab Scientist)
Institute Pasteur Korea (Asia)
Start : April 2013 | Status : Complete
The scientists: This project is about “Optimisation of a class of oxadiazole compounds targeting Mycobacterium tuberculosis inside macrophages” and is conducted by Jaime Escribano and Ms. Minjeong Seo. Jaime Escribano holds a PhD in Chemistry (Organic and Inorganic synthesis and catalysis) from the Department of Chemistry at the University of Burgos in Madrid. His colleague Minjeong holds a Masters in Chemistry from Korea University.
The sponsor: This collaboration with the Institute Pasteur Korea is led by Principal Investigator Dr Kevin Pethe a group leader of Antibacterial Drug Discovery and a coordinator of IP-K Drug Discovery Programs. The Institut Pasteur Korea (IP-K) is a non-profit organisation based in Seoul, South Korea. It was established in 2004 based on the collaboration agreement with a world-leading life sciences research institute, Institut Pasteur, and the Korean Ministry of Science, ICT and Future Planning. Integrating Institut Pasteur‘s 120 years+ of biotechnological knowledge with Korea’s state-of-the-art information technology and chemical research capabilities, IP-K has established itself as a well-renowned transnational research institute. With a focus on enabling technologies and therapeutics development in disease models pertaining to public health, IP-K leverages the systematic implementation of visual high throughput screening in conjunction with imaging approaches in critical steps of infectious and chronic disease. By enabling real-time observation of live disease cells,IP-K’s technology accelerates the drug discovery process, reduces its cost, opens the door to entirely new classes of drugs, and offers new insights into the mechanisms of disease.
Foundation funding: The Foundation is providing £131,167 in support.
GlaxoSmithKline’s contribution: GSK is providing in-kind contributions (including facilities and expertise from supporting scientists for HTS and GSK collection of compounds).
Project Description: There is an alarming increase in the number of cases of multi-drug resistant tuberculosis. This form of disease is particularly difficult to treat because the bacteria have become resistant to the most efficient antibiotics. Mycobacterium tuberculosis, the bacteria responsible for human tuberculosis is able to infect and hide in human macrophages (a cell of the immune defence system). Once inside a macrophage, the bacteria become naturally resistant to most anti-Tuberculosis drugs. The InstitutPasteur Korea recently discovered a new class of compounds that specifically kill Mycobacterium tuberculosis residing inside macrophages. During their time at the Open Lab, both Jaime and Minjeong are focusing their expertise in medicinal chemistry and cytotoxicity to enhance the efficacy and safety of this new class of compound.
“By developing a new class of drug, we hope to contribute to the development of the next generation of medicines that will be used to treat patients suffering from multi-drug resistant tuberculosis.” (Dr. Jaime Escribano, Open Lab scientist)
London School of Hygiene & Tropical Medicine-LSHTM (Europe)
Start : March 2013 | Status : Complete
The scientists: This project is led by Dr Rosario Díaz who has recently been joined by a second researcher, Dr Fernando Aguilar. The project focuses on drug discovery for leishmaniasis and is titled “Assay development of in vitro rates of death of intra-cellular Leishmania and Trypanosoma cruzi ” which aims to determine the replication rate of the intracellular forms of both of these parasites. This intracellular division rate is still undetermined but an understanding is essential when trying to establish a compound’s effect over time. Creating a detailed compound profile is the basis for progress in drug discovery.
The sponsor: The collaboration with the London School of Hygiene & Tropical Medicine (LSHTM) is led by Principal Investigators Professor Simon Croft and Dr Vanessa Yardley. The London School of Hygiene & Tropical Medicine is a world-leading centre for research and postgraduate education in public and global health. Its mission is to improve health and health equity worldwide; working in partnership to achieve excellence in public and global health research, education and translation of knowledge into policy and practice.
Foundation funding: The Foundation is providing £189,683 in support.
GSK’s contribution: GlaxoSmithKline is providing in-kind contributions (including facilities and expertise from supporting scientists for HTS and GSK collection of compounds).
Project Description: Leishmaniasis, a parasitic disease found in four continents, is the third most common cause of death caused by parasites in developing countries. Leishmaniasis has different clinical symptoms, and the visceral form, also known as kala-azar, is lethal if left untreated. Most existing treatments are expensive, with known toxicities and variable efficacy. There is increased resistance to these treatments for leishmaniasis. With research currently focused on developing an effective drug against these parasites, more compound profiling is required to characterise a fast-killing or time-dependent compound to help successful drug progression. At the Open Lab, the visiting scientists will seek to develop and validate an assay to measure the replication rate for intracellular parasites using fluorescent and qPCR methods.
“The collaboration with GSK is fundamental to my research, since their experience and know-how of the most modern and latest techniques and equipment will help us to develop the best assay. The equipment and facilities at Tres Cantos are simply not affordable for the academic community, and their support for our project is a boost to help us achieve our goals”. (Rosario Díaz, Open Lab scientist)
University of Minnesota (America)
Start : December 2012 | Status : Complete
The scientists: This project concerns “Antitubercular BirA inhibitors” and is being conducted by Curtis Engelhart, a scientist at the Center for Drug Design at the University of Minnesota. The research conducted by Curtis is focused on tuberculosis and seeks to exploit a recently-validated target for the discovery of a new antitubercular agent. Curtis holds a Bachelor of Science Degree in Chemistry from North Dakota State University and graduated in December 2012 with a Master’s of Science Degree in Medicinal Chemistry from the University of Minnesota.
The sponsor: This collaboration with the University of Minnesota is led by Principal Investigator Professor Courtney Aldrich. Founded in 1851, the University of Minnesota is ranked among the top public research universities in the United States. As a land-grant institution, the University of Minnesota is committed to engaging Minnesota, national and global communities to advance interdisciplinary knowledge; enhance students’ academic, civic, career, social and personal development; and apply intellectual and human capital to serve the public good.
Foundation funding: The Foundation is providing £109,801 in support.
GlaxoSmithKline’s contribution: GSK is providing in-kind contributions (including facilities and expertise from supporting scientists for HTS and access to the compounds library).
Project Description: BirA is an enzyme that links the bio-molecule biotin to Mycobacterium cellular proteins and controls Mycobacterium tuberculosis lipid metabolism. Before coming to the Open Lab to advance his research in the anti-TB compound library, Curtis optimised a cellular high throughput assay at the University of Minnesota.
The project’s overarching objective is to identify lead compounds which are active on this target (BirA). To help confirm activity on this target, scientists at the University of Minnesota have developed Mycobacterium tuberculosis mutants endowed with different expression levels of the BirA gene: deletion, under-expression and over-expression. During his time at the Open Lab, in addition to biochemical assays based on isolated BirA enzyme, Curtis is using these mutants to run cellular assays that will allow him to remove false positives.
“The open Lab offers us the technical expertise and equipment necessary to perform the research for this project. We would not be able to carry out this research project in our own academic research lab. The Open Lab provides the necessary equipment, resources, and expertise for the work – but it also provides an invaluable atmosphere of support, a center that works to find new treatments to combat diseases of the developing world.” (Curtis Engelhart, Open Lab scientist)
Seattle Biomedical Research Institute (America)
Start : November 2012 | Status : Complete
The researcher: Anuradha Kumar, a postdoctoral researcher working in a team led by Dr. David Sherman, Seattle Biomedical Research Institute, was responsible for conducting this research at the Open Lab.
The sponsor: Seattle BioMed is the largest independent, non-profit organisation in the US focused solely on infectious disease research. Our research is the foundation for new drugs, vaccines and diagnostics that benefit those who need our help most: the 14 million who will otherwise die each year from infectious diseases, including malaria, HIV/AIDS and tuberculosis. Founded in 1976, Seattle BioMed has nearly 350 staff members. By partnering with key collaborators around the globe, we strive to make discoveries that will save lives sooner.
Foundation funding: The Foundation provided £32,137 in support of this research.
GlaxoSmithKline’scontribution: GSK provided in-kind contributions (including facilities, chemical library and expertise from supporting scientists in the TB and Pharmacology units).
Project Description: The emergence of multi drug resistant Mycobacterium tuberculosis (Mtb) strains has highlighted the need for new medicines to treat TB. During her time at the Open Lab, Anuradha Kumar explored how new drugs can be discovered by taking advantage of previously validated drug targets that have not been the focus of current TB treatments.
With access to the large chemical library and the help of medicinal chemists, Anuradha was able to identify novel compounds that make good in-vivo candidates. In addition, these compounds will be optimised in collaboration with pharmacologists experienced with pre-clinical drug development to produce a new antitubercular lead compound with the most potential for success.
“The work at the Open Lab in Tres Cantos is highly collaborative - as well as working with highly skilled teams and the open access to different resources, scientists are able to move the project to experts who meet the specific needs as the research progresses.” (Anuradha Kumar, Open Lab scientist)
University of Liverpool (Europe)
Start : October 2012 | Status : Complete
The researcher: Matthew McConville, a postdoctoral researcher working in a team led by Dr. Paul O’Neill, associate professor, Dept. of Chemistry, will be responsible for conducting this research at Tres Cantos.
The sponsor: The University of Liverpool is one of the UK’s leading research institutions with an annual turnover of £410 million, including £150 million for research. Liverpool is ranked in the top 1% of higher education institutions worldwide and is a member of the Russell Group.
Foundation funding: The Foundation is providing £108,245 in support of the first year of research and £54,831 contingent on lead identification achievement.
GlaxoSmithKline’s contribution: GSK is providing in-kind contributions (including facilities and expertise from supporting scientists in Medicinal Chemistry and Pharmacology units).
Project Description: With rapidly spreading resistance to current antimalarial drugs, Matthew’s research is focused on finding new compounds to successfully treat and prevent malaria. Before beginning his research at the Open Lab, Matthew and his colleagues at the University of Liverpool examined 13,500 compounds that GSK had made publicly available and selected one series of compounds to conduct further research.
With the support of GSK scientists specialised in medicinal chemistry and pharmacology, Matthew’s research applies general synthetic organic chemistry processes to identify features of molecules which are important for antimalarial activity and are used to design more active compounds. If a lead compound with suitable properties is found, Matthew will be able to conduct further research aimed at target validation or lead optimisation.
“In addition to the scientific objectives of my project, I want to expand my knowledge of medicinal chemistry and gain experience of how drug discovery efforts are conducted in an industrial rather than an academic setting.” (Matthew McConville, Open Lab scientist)
University of Rome (Europe)
Start: September 2012 | Status: CompleteStart: September 2012 | Status: Complete
The scientist: Martina Cocozza, a pre-doctoral student working in a team led by Dr. Mariangela Biava (Sapienza University of Rome, Associate Professor at the Medicinal and Technological Chemistry department), is responsible for performing this project.
The sponsor: Sapienza University of Rome is the leading higher education school in Italy and also the largest University in Europe. It is also a member of several European networks. Sapienza carries out scientific research achieving high standards at national and international levels.
Foundation funding: The Foundation is providing £44,333 in support.
GlaxoSmithKline’s contribution: GSK is providing in-kind contributions (including facilities and expertise from supporting scientists in Medicinal Chemistry and Pharmacology units).
Project Description: Tuberculosis represents a never-ending challenge toward which research efforts are needed. There are some good reasons to intensify research: the last drugs were marketed over forty years ago and the current treatment time is too long and based on a combination of several old drugs. A recent challenge has been the appearance of multi drug resistance. For this purpose the researchers at Sapienza have identified some pyrrole molecules that showed interesting antimycobacterial properties in preliminary studies. The aim of the work being carried out at the Open Lab is to study ADME properties of these compounds and reach a new lead with better pharmacological properties than those of the antibiotics in use.
“The Tres Cantos Open Lab Foundation is providing me with a great opportunity to advance my research which is likely to help me obtain results much quicker than I could ever have achieved at my research institute”. (Martina Cocozza, Open Lab scientist)
Omnia Molecular (Europe)
Start : April 2012 | Status : Complete
The scientists: Lluís Benitez, was a research associate working in a team led by Dr Lluís Ribas (Omnia, CSO), and was responsible for setting up the HTS screening platform at the Open Lab in Tres Cantos.
The sponsor: Omnia Molecular was founded in 2005 by Dr Lluís Ribas and is a spin-off from his work as principal investigator at the Barcelona Institute for the Research in Biomedicine. He has 18 years’ experience with Aminoacyl-tRNA synthetases at the Massachusetts Institute of Technology (1993-1997) and The Scripps Research Institute (1997-2003). Omnia Molecular designs and develops novel anti-infectives targeted at difficult-to-treat infections in hospital, in particular those caused by pathogens that have developed resistance to existing antibiotics. Omnia's business model is to co-develop projects with pharma industry partners and out-license pre-clinical candidates after proof of efficacy in animal infection models.
Foundation funding: The Foundation provided £75,560.
GlaxoSmithKline’s contribution: GSK provided in-kind contributions (including facilities and expertise from supporting scientists to run the HTS from GSK’s collection of compounds).
Project Description: Tuberculosis is an old disease which continues to represent a significant challenge for global health affecting 10 million people and killing 2 million people each year. The emergence of multi-and extensive drug-resistance is a major problem, the cause of which is largely attributed to the misuse of antitubercular agents. At the moment, treatment is comprised of a combination of at least three different drugs that must be taken for a period of six months or longer. The burdensome side effects and the length of treatment often means patients don’t finish the course, which leads to a rise in drug-resistant strains. During his time at the Open Lab, Lluís focused on finding new classes of antibiotics to treat TB over a shorter period of time. Lluís ran a High Throughput Screening (HTS) of GSK´s compound sets to provide new starting points for the identification of potent and selective inhibitors against TB.
"Without access to GSK’s HTS facilities and extensive compound library advancing my research would be very difficult.” (Lluís Benitez, Open Lab scientist)
New York University, School of Medicine (America)
Start : April 2012 | Status : Complete
The Researcher: Julio Alonso Padilla, a research associate working in a team led by Dr. Ana Rodriguez, associate professor, NYU School of Medicine, will be responsible for running primary HTS at Tres Cantos.
The sponsor: NYU School of Medicine is one of the US premier centres of excellence in healthcare, biomedical research and medical education. The Medical Parasitology laboratory headed by Ana Rodriguez studies two different parasites, Plasmodium, which causes Malaria, and Trypanosoma cruzi, involved in Chagas disease. One of the group’s main interests is the development of effective drugs against Chagas Disease.
Foundation funding: The Foundation is providing £85,570 in support.
GlaxoSmithKline’s contribution: GSK is providing in-kind contributions (including facilities and expertise from supporting scientists for HTS and GSK collection of compounds).
Project Description: At the Open Lab, Julio is running a specific test known as a Trypanosome cell-based assay to help identify new drugs for the treatment of Chagas disease. A significant part of his research involves conducting high-throughput screening (HTS) to find specific inhibitors of the infection.
The objective of the HTS is to find several chemical compounds which demonstrate specific activity relevant to Chagas disease that could subsequently be developed into a lead for the treatment of this disease.
“This type of screening is only possible with access to facilities at a large pharmaceutical company such as GSK. The amount of resources, equipment and expertise needed to screen a compound collection of the size that will be analysed in this campaign, would be unfeasible elsewhere”. Julio Alonso Padilla (Open Lab Scientist)
University of Durham (Europe)
Start : December 2011 | Status : Complete
The scientists: Jennifer Norcliffe, MSci graduate in Natural Sciences (Biology and Chemistry) and currently pursuing a PhD at Durham University and John Mina, PhD in Chemical Biology were the visiting researchers from Durham University where they worked in a team led by Drs Paul Denny (Senior Lecturer in Parasitology) and Patrick Steel (Senior Lecturer in Chemistry) at the Biophysical Sciences Institute laboratories in the Department of Chemistry at Durham University
The sponsor: Durham University is England’s third oldest university based at a UNESCO World Heritage Site that is jointly owned with Durham Cathedral. It is a world top 100 university with a global reputation and performance in research and education. The Department of Chemistry at Durham is one of the UK leading centres for chemical sciences and has a long tradition of interdisciplinary research. It is an integral component of the Biophysical Sciences Institute.
Foundation funding: The Foundation provided £61,555.
GlaxoSmithKline’s contribution: GSK provided in-kind contributions (including facilities and expertise from supporting scientists for HTS and GSK collection of compounds).
Project Description: Leishmaniasis, Chagas Disease and Human African Trypanosomiasis (African sleeping sickness) are neglected tropical diseases caused by infections spread by kinetoplastid parasites. All are potentially fatal but treatments are expensive and not widely available. Emerging resistance is also a problem and therefore new and inexpensive therapeutic treatments are urgently needed
Supported by GSK scientists specialised in screening and compound profiling, John and Jennifer used the automated screening equipment and GSK’s extensive compound library to design and run a high-throughput yeast-based assay in order to identify inhibitors of the target enzyme in the kinetoplastid parasite that could be a target for new treatments.
This research helped identify 500 compounds that displayed a high degree of activity against relevant enzymes. From the 500 compounds identified by screening, 216 have been selected for further investigation. This next stage of research includes both biochemical screening and activity determination against both insect-stage and host-stage parasites. The most promising hits will be subjected to further tests in order for the best lead-like candidate to be produced.
“GSK’s involvement has been vital in moving this project forward. It would have been impossible to undertake a screen of this magnitude without the specialised equipment they supplied.
The provision of GSK’s own compound library has enabled us to identify a much larger number of diverse chemical entities than we would otherwise been able to discover, increasing our chances of identifying and developing suitable lead-like compounds in the future.
As an academic institution, access to a compound library of this size and equipment capable of ultra-high-throughput screening is unprecedented. The Tres Cantos Open Lab Foundation also afforded our group the opportunity to undertake work that would be difficult to fund through conventional mechanisms such as Research Councils UK. On a personal level, at such an early career stage it was an incredible opportunity to acquire new skills and to work alongside and learn from industry experts” (Jennifer Norcliffe, Open Lab scientist).
Northeastern University, USA and CSIC, Spain (America, Europe)
Start : December 2011 | Status : Complete
The scientists: Rosario Diaz, PhD, a research associate working in a team led by Dr Miguel Navarro (IPBLN-CSIC), performed the high throughput screening (HTS) and follow-up biological assays for the program. Two chemists, Joao Sexias, PhD and Sandra Luengo, PhD, worked alongside GSK medicinal chemists to perform hit validation and follow-up medicinal chemistry, with the efforts driven by Professor Michael Pollastri (Northeastern University Department of Chemistry & Chemical Biology.)
The sponsor: Founded in 1898, Northeastern is a global, experiential, research university located in Boston. Northeastern is the recognised leader in experiential learning, anchored in the world’s largest and most innovative cooperative-education programme. The Institute of Parasitology and Biomedicine "López-Neyra" (IPBLN) belongs to the Spanish National Research Council (CSIC). Since its foundation more than fifty years ago as the National Institute of Parasitology, the IPBLN houses a significant number of laboratories studying various aspects of molecular parasitology with a high capacity to work in collaboration. The objectives of the research activity include the identification of new protein targets for drug development and new molecular tools for the treatment of infectious diseases.
Foundation funding: The Foundation provided £143,295 in support.
GlaxoSmithKline’s contribution: GSK is providing in-kind contributions (including facilities and expertise from supporting scientists for HTS and GSK collection of compounds).
Project Description: The protozoan parasite Trypanosoma brucei is an insect-borne pathogen that causes human African trypanosomiasis (HAT), which is commonly referred to as African sleeping sickness one of the world’s neglected tropical diseases, found in sub-Saharan Africa. The main problem the researchers tried to address is the lack of safe and effective treatments against this disease. A collaboration between investigators at Northeastern University in Boston and at the Institute of Parasitology and Biomedicine of the Spanish National Research Council (IPBLN-CSIC) in Granada identified a potent inhibitor of parasite growth among established classes of inhibitors of human kinase enzymes. Inspired by this initial success, Joao, Rosario and Sandra assessed more than 30,000 compounds in the GSK chemical library for their ability to suppress the spread of the harmful parasite that penetrates the central nervous system, where T. brucei, thepathogen which causes this potentially lethal disease, resides.
“This research would have taken much more time without access to GSK’s resources and expertise in miniaturisation technology which is fundamental to boost research in the diseases of the developing world.” (Rosario Diaz, Open Lab scientist)
CRESIB, Spain (Europe)
Start : June 2011 | Status : Complete
The scientists: Two scientists are involved in this project: Richard Thomson, PhD and Nuria Antón, PhD. Nuria will spend most of her time in Tres Cantos, while Richard Thomson is dividing his time between Tres Cantos, with Dr. Hernando del Portillo at CRESIB, and the institute FMT-HVD in Manaos, Brazil, which sees around one third of P vivax malaria cases in Manaos and where attempts to establish the culture will be made in collaboration with the group of Dr. Marcus GV Lacerda.
The sponsor: The Barcelona Centre for International Health Research (CRESIB) is a global health research institute developed from some of the leading academic and biomedical research institutions in Barcelona: Universitat de Barcelona, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and the Catalan government.
Foundation funding: The Tres Cantos Open Lab Foundation is providing £266,850 funding for this project.
GlaxoSmithKline’s contribution: GSK has a group working on the P.vivax culture and the CRESIB and GSK scientists will work in close collaboration. This project will require work in the GSK Biosafety level 3 facilities at Tres Cantos.
Project Description: This two-year project is focused on creating a continuous lab-based supply of the P. vivax malaria parasite in the blood stage. If successful this project will offer a technological breakthrough that could facilitate further advances in research on P. vivax and potentially lead to a new era in P.vivax malaria drug discovery.
"Without GSK’s support, we would not be able to conduct this research. The access to resources at the Tres Cantos facility and expertise of GSK’s scientists are invaluable to helping us achieve our project’s objectives”. (Richard Thomson, Open Lab scientist)
CICBIOGUNE, Spain (Europe)
Start : April 2011 | Status : Complete
The scientists: Lydia Mata, a biologist with a Masters in pharmaceutical sciences worked alongside the Malaria and TB Drug Discovery teams at the Open Lab in Tres Cantos.
The sponsor: CICbioGUNE (Center for Cooperative Research in Biosciences), a non-profit biomedical research organisation, founded in 2002 by the Department of Industry of the Basque Government, opened its research facilities at the Technology Park of Bizkaia in January 2005.
Foundation funding: The Foundation provided £95,875 funding.
GlaxoSmithKline’s contribution: GSK provided in-kind contributions (including facilities for parasite in vitro culture).
Project Description: The objective of this project was to characterise the ubiquitylation profiles of cells infected by multiple drug resistant tuberculosis and the malaria parasite P.falciparum. Ubiquitin is a small regulatory protein that is found in almost all organisms. Ubiquitin binds proteins (a process known as ubiquitylation), thus marking them for destruction or directing proteins to other locations in a cell, where they control other biological processes. The ubiquitylation systems of both the malaria parasite, Plasmodium, and the TB organism Mycobacterium are involved in pathogen replication and infection, so gaining an understanding of these systems in the infected cells could help uncover new approaches for medicines designed to treat malaria and TB.
“This research enabled us to obtain samples from plasmodium falciparum infected cells that are being analysed for ubiquitylated proteins by mass spectrometry at the Open Lab in Tres Cantos. The results of this analysis could provide some potential new targets. This research has also generated new protocols which can benefit other related projects carried out by the DDW community more broadly. These protocols will be publicly available to the scientific community following their publication.”
“This project would not have been possible without access to GSK´s resources and facilities which were crucial to advance our research as we did not have the required knowledge or facilities to work with the pathogens, plasmodium falciparum and mycobacterium tuberculosis.” (Lydia Mata, Open Lab scientist)
Birmingham University (initially Swiss Federal Institute of Technology in Zürich - ETHZ) - Optimisation of Fidaxomicin analogs (Europe)
Start : June 2016 | Status : Complete
The scientists: Stefan Jackenroll
The sponsor: Birmingham University (initially Swiss Federal Institute of Technology in Zürich - ETHZ)
Foundation funding: The Foundation is providing £134,240 in support, together with co-funding from the European Union FP7 program through its COFUND scheme.
Project Description: The rise of multi-drug- and extensively-drug-resistant mycobacterial strains increasingly hampers current TB treatments. The development of new drugs is therefore highly sought after.
The DNA-dependent RNA polymerase (RNAP) plays a fundamental role in the transcription cycle and is essential for all living organisms. Bacterial RNAPs differ structurally and functionally from their eukaryotic counterparts and thus represent interesting drug targets. Since the RNAP of Mycobacterium tuberculosis constitutes the target of the natural product analog Rifampicin, it is clinically validated but largely underexploited in TB-drug discovery.
Fidaxomicin is a known RNAP-inhibitor of several gram-positive bacteria which is also named Lipiarmycin A3 or Tiacumicin B. It is clinically applied against Clostridium difficile infections and shows promising in vitro activity against Mycobacterium tuberculosis (MICH37Rv = 0.085-3.1 µg/mL).[6-8] Additionally, Fidaxomicin exhibits good activity against a number of multi-drug-resistant TB strains (see appendix I), no cross-resistance to rifampicin or other front-line TB-drugs and a low frequency of spontaneous resistant mutants ( ̴1 in 108 cells/mL).
With this data in hand, we believe that the natural product Fidaxomicin represents a promising starting point for a TB optimisation programme.
NEU/CSIC - T. brucei drug discovery: ADMET and PK support for hit-to-lead optimization (Europe)
Start : March 2016 | Status : Complete
The scientists: N/A
The sponsor: NEU/CSIC
Foundation funding: The Foundation is providing £99,100 in support.
- Expertise in drug discovery (included ADMET expertise) with the aim of accelerating the discovery of a pre-candidate for HAT
- Performance of in vitro ADME experiments (solubility, permeability, microsomal stability, plasma protein binding, MDCK-MDR1, CYP inhibition; up to 3-5 compounds/mo)
- Mouse PK experiments at GSK, with plasma drug levels (up to 10 per year).
- Safety profiling (EXP) – up to 4 compounds/year
- GSK is assembling a “HAT-box” with 192 compounds with submicromolar activity against Tbb and selectivity over human cells coming from the HTS campaign of the GSK collection. These compounds could be used also as starting points if needed.
Project Description: From December, 2011 - March, 2013 a TCOLF-funded collaboration between GSK-Tes Cantos, Northeastern University (NEU), and CSIC was undertaken in order to assess a kinase targeted library for anti-T. brucei activity. Following the screening of ~42k compounds, the project team identified 797 potent (pIC50>6), selective (>100x over HepG2 cells) inhibitors of T. brucei growth in vitro. These compounds were characterized in terms of their rate of killing, reversibility (cidality), and for their computed properties (including prediction of CNS penetration). These culminated in mouse PK studies, and efficacy was demonstrated for one HTS hit (SB-443342), which effected cure of a bloodstream infection following an IP dosing regimen at 10 mg/kg. (PLOS-NTDs, 2014 e3253). On the strength of these data, the NEU and CSIC investigators have secured five years of funding from the US NIH ($2.5 million award total costs) to translate these hit compounds into advanced lead compounds that show potent and non-toxic efficacy in mice with CNS T. brucei infections following oral dosing. The main objective of the Open Lab is to assess the likelihood of these leads to be Candidates, with that aim and given the difficulties associated with accessing some of the required drug discovery expertise and capacity in an academic environment and the unique value offered through the Open Lab program, we now request periodic support for the ADME, PK, and toxicity studies needed in order to advance this project towards the delivery of a clinical candidate against sleeping sickness
University of Birmingham - Hit-to-lead optimisation of a small-molecule inhibitor targeting the M. tuberculosis aspartyl-tRNAAsp synthetases (Europe)
Start : Sept 2014 | Status : Complete
The scientists: Stefan Jackenroll
The sponsor: University of Birmingham
Foundation funding: The Foundation is providing £124,428 in support.
GSK’s contribution: GSK’s contribution to the project will be in kind, and their expertise in hit-to-lead optimisation of small molecules including access to both in vitro and in vivo DMPK and efficacy studies.
Project Description: Current TB treatment programmes are losing their efficacy, due, at least in part, to the rise of multi-drug- and extensively-drug-resistant TB. It is therefore essential that new drugs, ideally with novel targets, be developed. In light of their involvement in protein biosynthesis, aminoacyl-tRNA synthetases (aaRSs) are very attractive drug targets ; indeed, several natural products and non-hydrolysable aminoacyl adenylate analogues have been shown to inhibit this class of enzyme in vitro; however, further development of these inhibitors has often been thwarted by their inability to penetrate the bacterial cell envelope effectively and by cross-reactivity against other protein targets. We, and very recently, Sacchettini , have independently shown that compound A possesses whole-cell anti-tuberculosis (TB) activity by targeting M. tuberculosis AspRS. A represents a novel structure for an aaRS inhibitor and is the first such inhibitor of M. tb AspRS. We now seek to undertake a hit-to-lead optimisation of A to accelerate the potential of developing this class of inhibitor against a novel and demonstrably essential M. tuberculosis target.
McGill Univ/Edinburgh Univ - Targeting the trypanosome editosome for drug discovery (Europe)
Start : July 2013 | Status : Complete
The scientists: Vaibhav Mehta
The sponsor: McGill Univ/Edinburgh Univ
Foundation funding: The Foundation is providing £57,800 in support.
GSK’s contribution: GSK’s scientific expertise and capabilities in high throughput screening as part of a collaborative approach to drug discovery against the editosome. We would also like to discuss options for ongoing support for hit-to-lead development (including SAR and medicinal chemistry) on a collaborative basis.
Project Description: The major trypanosomatid human pathogens, Trypanosoma brucei, T. cruzi, and Leishmania spp. are the causative agents of African sleeping sickness, Chagas disease, and leishmaniasis, respectively. Trypanocidal drugs used to treat these parasitic illnesses are often toxic, not very effective, and have led to the emergence of drug resistant parasites. Creating new, effective, and safe drugs for the treatment of trypanosomiases is of prime importance. One of the essential molecular mechanisms unique to trypanosomatid parasites is RNA editing. This process converts untranslatable mitochondrial mRNA precursors of multiple components of the energy-generating oxidative phosphorylation system into translatable mature mRNAs. Modifications required during RNA editing to obtain translatable mRNA are catalyzed by a multi-protein complex called the editosome. About 20 proteins are identified as components of the editosome while other proteins play accessory roles. Little is known about how these components work together. All the catalytic core activities of the editosome, including RNA editing ligase 1 (TbREL1), are known to be essential for both the mammalian and insect life cycle stages of the parasite. We have developed highly sensitive and simple “mix and measure” assays for high throughput screening of chemicals that can inhibit the editosome function or, specifically, TbREL1. We will use these assays to identify potent and specific editosome / TbREL1 inhibitors, which will not only facilitate a hypothesis driven analysis of editosome assembly and function but also the discovery of novel inhibitor compounds that can ultimately be effective against all three major trypanosomatid pathogens.
Florida International Univ - Identification of inhibitors of M tuberculosis topoisomerase I for novel anti-TB therapy (America)
Start : Sept 2013 | Status : Complete
The scientists: Neelam Keshwani
The sponsor: Florida International Univ
Foundation funding: The Foundation is providing £45,563 in support.
GSK’s contribution: GSK would contribute the chemical library for HTS screening. GSK is to provide available nearest neighbors and any information on the identified hits if possible. Medicinal chemistry support or disclosure of synthetic routes to the original hits from GSK is needed first for the resynthesis of the selected hits, and subsequently for SAR to improve the potency and selectivity of validated hits in collaboration with TB Alliance.
Project Description: Topoisomerase poison inhibitors are highly effective for initiating cell death in anti-bacterial and anti-cancer therapy. These inhibitors lead to the accumulation of the covalent intermediate formed between topoisomerases and cleaved DNA. Every organism must have at least one type IA topoisomerases to resolve topological barriers encountered in DNA replication, recombination, repair that require cleavage and rejoining of a single DNA strand. The type IA topoisomerase in M. tuberculosis, Mtb topoisomerase I (MtbTopI), has been shown in genetic studies to be essential for survival. This enzyme has been characterized biochemically and represents a novel target for development of drugs to be used in new combination therapy for treatment of XDR and MDR TB. A fluorescent assay suitable for HTS has been developed for identification of small molecules that can act as poison inhibitors against MtbTopI. The proposed project would utilize this HTS assay to identify compounds from the GSK corporate chemical library at the Open Lab facilities, including the anti-tubercular subset. In our preliminary screen in collaboration with TB Alliance several hits active against TB have been identified and they have been used in the hit expansion exercise. The identified hit compounds will be confirmed for activity as poison inhibitors of MtbTopI in secondary biochemical and cell based assays. An active compound targeting MtbTopI as mode of action for anti-TB activity will be used as starting point for development of a potent and non-toxic compound for new TB therapy in collaboration with TB Alliance and medicinal chemists at GSK.
CNRS / Institut de Biologie Structurale and Harvard Medical School - Biochemical and Structural Characterization of Mtb ClpC1P1P2 and ClpXP1P2 inhibitors - first step towards new TB therapeutics (CPPI) (America, Europe)
Start : November 2016 | Status : Complete
The scientists: Dr. Hugo Duarte de Carvalho Fraga is a biochemist with extensive experience in enzymology and structural biology. Hugo obtained his PhD in 2007 from the department of chemistry of the Faculdade de Ciências da Universidade do Porto. In 2015, Hugo joined the Goldberg Lab at Harvard Medical School to work on mycobaterial ClpP1P2 complexes.
Foundation funding: The Foundation is providing £238,110 in support, together with co-funding from the European Union´s FP7 program through its COFUND scheme.
GSK’s contribution: GSK is providing expertise and know-how on post-screening processes, including hit characterization, medicinal chemistry and enzymology.
Project Description: About 10 million people worldwide fall ill from tuberculosis every year, and it has been estimated that one third of all humans is infected with latent Mycobacterium tuberculosis (Mtb). Moreover, Mtb has become increasingly resistant to available antibiotics. Consequently, it is important to identify and characterize new therapeutic targets in Mtb and to synthesize selective inhibitors. ClpP1, ClpP2 and their associated chaperones, ClpX and ClpC1 are required both for the growth of Mtb and for its virulence during murine infection and are highly attractive drug targets, especially since they are not present in the cytosol of mammalian cells, and they differ markedly from the mitochondrial ClpP complex.
The purpose of this projects is to characterize hits from the HTS being conducted at the Open Lab to discover compounds able to inhibit protein degradation by the ClpC1P1P2 complex, and to determine their mode of action. The binding site and structural effects of the hits in ClpC1, ClpX and CpP1P2 will be evaluated using state of art NMR approaches. This project results from collaboration between the Goldberg Lab, Harvard Medical School (HMS) and the Institut de Biologie Structurale (IBS), Grenoble, France and should promote the development of more potent drug candidates.
University of Birmingham - Exploring TB Space: Optimization of novel, high quality phenotypic hits (EXPTBS) (Europe)
Start : October 2016 | Status : Complete
The scientists: Dr. Jorge Hernández will focus his research on the optimization of valuable novel Mycobacterium tuberculosis (Mtb) phenotypic active hits with promising developability profile. Jorge is an organic chemist by training and will be working under the supervision of Prof. Gurdyal Besra from the University of Birmingham.
The sponsor: School of Biosciences, University of Birmingham
Foundation funding: The Foundation is providing £102,849 in support, together with co-funding from the European Union FP7 program through its COFUND scheme.
GSK’s contribution: GSK will contribute its extensive medicinal chemistry knowledge in hit-to-lead whole cell programs for TB.
Project Description: Mtb phenotypic high-throughput screening (HTS) represents the main source of new chemical entities (NCE), although a major challenge resides in their successful optimization and mechanism of action (MoA) elucidation. The high level of attrition in early drug discovery stages is often due to the lack of validated hit series with good physicochemical and pharmacokinetic properties. Therefore, selection and optimization of valuable starting points with an understanding of the MoA is extremely crucial. Following recent release of phenotypic confirmed actives from a screening of the GSK library, a selection of 10 starting points, considered tractable and less explored within the TB published chemical space, has been made. The selection was largely based on developability criteria. The first stage of this project will involve an initial prioritization of 3 series which will then be progressed into a more focused hit to lead campaign, to deliver lead candidates with suitable MIC potency and DMPK profile to support evaluation of in vivo efficacy.
University of Birmingham - Whole cell protein synthesis inhibition assay for high-throughput drug discovery (Europe)
Start : September 2016 | Status : Complete
The scientists: Dr Gurcha is a Post-Doctoral Researcher in the Institute of Microbiology and Infection at the University of Birmingham (BHAM), UK. After graduating from the University of Newcastle with a PhD in Microbiology, he continued his academic training under the supervision of Prof Gurdyal S. Besra aimed at understanding the biochemistry and molecular genetics of cell wall assembly in Mycobacterium tuberculosis, the causative bacterial agent of tuberculosis infections. His current research focuses on developing protein synthesis inhibition assays to identify drugs against M. tuberculosis. In addition, she is also interested in hydrophobic cell surface properties of various Mycobacterium species as it may prove useful in determining the role of cell envelope to pathogenesis and treatment of mycobacterial infections.
The sponsor: University of Birmingham
Foundation funding: The Foundation is providing £102,849 in support.
GSK’s contribution: GSK is providing expertise in High Throughput Assays (HTA) and access to Biosafety Level 3 facilities and GSK’s collection of compounds.
Project Description: Our aim is to conduct a phenotypic high-throughput screen of the “TB box”, a set of known M. tuberculosis inhibitors from the GSK collection. BHAM have developed a novel whole cell reporter assay for protein synthesis inhibition in mycobacteria, such as M. bovis BCG and M. tuberculosis. This assay utilises anhydrotetracycline-inducible mCherry expression that, in the presence of a dose response ribosomal inhibitors, produces a dose-dependent reduction in fluorescent output, which can be monitored by an automatic fluorimetric plate reader. This assay will provide an insight into the mode of action of hit compounds, which can be further validated biochemically and by the generation of spontaneous resistant mutants and whole genome sequencing. This work will be used to compliment a biochemical ribosomal HTS being conducted by Prof. Sacchettini´s group, wherein phenotypic hits will be validated for target engagement in the biochemical assay at Texas A&M University.
University of British Columbia - Intra-macrophage driven optimization of confirmed hit GSK421197A (America)
Start : June 2016 | Status : Complete
The scientists: Dr. Abraham Lopez will focus his research on the optimization of several hits coming from intracellular high-throughput screening (HTS) against Mtb-infected macrophages. Abraham is a Postdoctoral Researcher with significant previous experience in drug discovery, working under the supervision of Prof. Av-Gay. He is an organic/medicinal chemist by training, and his primary objective in this project will be the delivery of new compounds with good activity in macrophages, acceptable ADME and safety profiles, and with a potential indication of in vivo efficacy for further progression to a lead optimization stage.
The sponsor: University of British Columbia
Foundation funding: The Foundation is providing £135,680 in support, together with co-funding from the European Union FP7 program through its COFUND scheme.
GSK’s contribution: GSK will contribute its extensive biological and medicinal chemistry experience in whole cell programs for TB (ChemMedChem 2013,8, 313; PlosOne, PLoS One 2013, 8(4), e60933) and will provide access to the existing tools for the drug discovery process.
Project Description: The phenotypic approach for the discovery of new anti-TB drugs relies on the screening of compound libraries against Mtb in in-vitro artificial growth conditions. However, those conditions do not resemble the physiological environment in human macrophages, which is one of the hallmarks of Mtb pathogenesis. The group of Prof. Av-Gay has recently carried out a TCOLF-funded HTS against Mtb-infected human macrophages. This activity led to promising identified hits, showing inhibition of bacteria growth at low micromolar concentrations with a remarkable 2 orders of magnitude increase in intra-macrophage activity compared to the in-vitro whole cell assay. The initial stage of this program will involve early stage in-vitro TB biology and ADMET profiling of selected hits. Initial synthetic efforts will focus on a limited set of target compounds to define the minimum pharmacophore, identify issues and demonstrate the scope for a more extensive hit to lead (H2L) plan to address the issues. The H2L process typically requires a number of synthesis rounds (≈50 compounds). In order to enter lead optimization, the series should be significantly de-risked, demonstrated in-vivo efficacy and have a suitable probability of delivering an optimized lead compound. In addition to this work, a detailed study on the mechanism of action will be carried out in parallel, potentially leading to the discovery of a novel drug target for TB.
University of Birmingham - ChemPro_Target_ID - A Chemical Proteomics Approach to Confirm – or Otherwise – the Results of Whole-Genome Sequencing of Spontaneous Resistant Mutants Generated Against Hits from a Phenotypic Screening Campaign: Is MmpL3 Really the Target for Such a Diverse Range of Structures? (Europe)
Start : June 2016 | Status : Complete
The scientists: Dr. Alejandro Cabanillas will focus his research on the application of an innovative chemical proteomics ligand–protein capture technology to identify the putative protein targets of different antitubercular drug leads.
Alejandro is a Research fellow at the University of Birmingham with previous experience in cancer drug development under the supervision of Dr. Sam Butterworth. He is an organic chemist by training, and his primary role in this project will be the design, synthesis, and optimisation of linkable analogues of the antitubercular leads for proteomics profiling.
The sponsor: University of Birmingham
Foundation funding: The Foundation is providing £148,782 in support, together with co-funding from the European Union FP7 program through its COFUND scheme.
GSK’s contribution: GSK will contribute its extensive experience in medicinal chemistry and Cellzome´s chemical proteomics platform (Nat Microbiol. 2016, doi:10.1038/nmicrobiol.2015.6).
Project Description: Leads compounds identified from whole-cell phenotypic screening campaigns provide a privileged starting point for TB drug discovery programmes. The success of this approach, however, relies on efficient strategies for elucidating the cellular targets of these leads. In many instances, target identification rests on the generation of spontaneous drug-resistant mutants, with the expectation that resistance-conferring mutations, revealed by whole-genome sequencing, identifies the protein target of a given hit. However, as resistance can occur through various mechanisms, spontaneous drug-resistant mutations may not only arise in the drug target but also in other cellular proteins that interact with the inhibitor.
A number of structurally diverse lead compounds have been found to generate mutations in the RND family transporter MmpL3, implicating this essential protein as their target. A novel chemical proteomics ligand–protein capture approach has been used to confirm whether or not this was the case for the THPP series (Nat Microbiol. 2016, doi:10.1038/nmicrobiol.2015.6). This study found that this promising class of inhibitor actually targets the cytoplasmic protein EchA6. Some of ‘MmpL3 inhibitors’, identified through whole genome sequencing of spontaneous drug-resistance mutants, may actually act against other protein targets. The aim of this project is to apply the novel chemical proteomics technology, developed by GSK-Cellzome, to other putative MmpL3 inhibitors to confirm whether this is indeed the case.
IQUIBICEN-CONICET, Dept of Biological Chemistry, School of Exact and Natural Science, University of Buenos Aires. (America)
Start : June 2016 | Status : Complete
The scientists: Estefanía Urdániz is a PhD Student in the IQUIBICEN- Department of biological chemistry, University of Buenos Aires, supervised by the PI of the project Dr. Mariana Piuri.
Estefania has constructed a new improved generation of FP carrying a modified mCherrybomb gene. Also, she set up the conditions for detection of M.tb by automated fluorimetry for extracellular activity testing of compounds. Phage infection in a multiwell format was standardized and MICs were determined for a wide range of drugs currently used for TB treatment with different targets in the bacteria. Recently, she has been working on the development of an infection assay in eukaryotic cells, using macrophages and pulmonary epithelial cells. She is also working in the automatization of this cell infection assay for intracellular screening of several compounds at the same time.
The sponsor: IQUIBICEN-CONICET, Department of Biological Chemistry, School of Exact and Natural Science, University of Buenos Aires.
Foundation funding: The Foundation is providing £40,636 in support.
GSK’s contribution: Access to GSK TB compounds set for screening. GSK will also contribute its extensive experience in extracellular and intracellular in vitro compound screening against Mycobacterium tuberculosis. GSK will also provide its expertise in in vivo studies and access to facilities for in vitro and in vivo studies.
Project Description: Tuberculosis (TB) is a major cause of human mortality; approximately two billion people are infected with the causative agent, Mycobacterium tuberculosis (M.tb). The emergence of resistant strains has become a serious public health problem worldwide complicating treatment and control of the disease. The development of reporter mycobacteriophages was described as a simple means of revealing the metabolic state of M. tb cells, and therefore their response to antibiotics. Based on this innovative approach, our aim is to develop a simple and rapid methodology that can speed the process of discovery of new anti-TB drugs. This phage-technology can be used for both in vitro and in vivo activity testing of compounds in a full-scale, fast and sensitive assay.
London School of Hygiene and Tropical Medicine (LSHTM) - Mode of action and target identification of anti-Chagasic compounds (Europe)
Start : May 2016 | Status : Complete
The scientists: Dr. Francisco Olmo will exploit high-throughput genetic technologies to identify genes involved in resistance to anti-T.cruzi lead compounds belonging to the GSK Chagas Box recently published. Francisco is a Postdoctoral Researcher at LSHTM, working under the supervision of Prof. John Kelly. He is a biochemist/molecular biologist by training with first-hand experience in kinetoplastid biology. Francisco has carried out placements in several international labs
The sponsor: London School of Hygiene and Tropical Medicine (Department of Pathogen Molecular Biology)
Foundation funding: The Foundation is providing £176,250 in support, together with co-funding from the European Union FP7 program through its COFUND scheme.
GSK’s contribution: GSK will provide its experience in lead discovery and compound profiling stemming from phenotypic hits, as recently published (Scientific Reports 5:8771, March 2015. DOI: 10.1038/srep08771). This experience will be leveraged in terms of examining phenotypically transformed parasite clones selected by the scientist for resistance to compounds in the Chagas-Box at GSK lab. Extensive screening by High Content Imaging Assays will be carried out against intra and extracellular forms.
Project Description: The aim of the project will be to add value to the lead optimization process by identifying the intra-parasite targets of compounds showing most therapeutic promise, deciphering their mechanisms of action, and assessing the potential for resistance.
Identification of genes involved in resistance to novel compounds from the HTS formerly prosecuted at GSK will be approached through complementary high-throughput genetic methodologies, such as RITseq in T. brucei, CRISPR/cas9 in T. cruzi and construction of a T. cruzi cosmid over-expression library. The set of genetic constructs will be screened against GSK Chagas Box in order to assess the modes of action and/or resistance mechanisms of lead compounds in T. cruzi. Furthermore, in vivo screening can be undertaken to assess physiological relevance
“Severo Ochoa” Molecular Biology Center and University of León - Small-molecule screening against Visceral Leishmaniasis using ex-vivo splenic explant cultures
Start : January 2016 | Status : Complete
The scientists: Raquel Alvarez Velilla is a Postdoctoral Researcher at the Severo Ochoa Molecular Biology Center and University of León, working under the supervision of Prof. Rosa Reguera and Prof. Manuel Fresno. She is a molecular and cellular biologist by training with experience in Leishmania infection. Her primary role in this project will be to study two different intracellular screening approaches against Leishmania.
Foundation funding: The Foundation is providing £220,510 in support
GSK’s contribution: GSK will provide compounds for their evaluation as anti-Leishmanials in addition to its extensive experience in phenotypic-based screening programs for Visceral Leishmaniasis [Scientific Reports (2015) doi:10.1038/srep08771; Antimicrob. Agents Chemother. (2016) doi:10.1128/AAC.01781-15].
Project Description: The approach will compare two in vitro assays based on Leishmania intracellular infections in established cell lines vs primary cultures (spleen explants). A high throughput platform will be accessed as part of the first approach, while 3D-primary cultures containing the elements responsible for the immune response will be used in the second approach. Previous methodologies for screening small molecules, while effective, have partly overlooked the important role of the immune system in the identification of compounds against Leishmania infection. The project aims to capture the potential host contribution in an assay that could help identify novel leads for the treatment of Leishmania.
London School of Hygiene and Tropical Medicine - Screening and identification of inhibitors of the Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) as novel antimalarial drugs (Europe)
Start : October 2015 | Status : Complete
The scientists: Dr Maria Penzo will focus her research on the discovery of new antimalarial drugs, through a CoFund project titled "Screening and identification of inhibitors of the Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) as novel antimalarial drugs”. Maria is a Postdoctoral Researcher in the research group of Prof. David Baker at the London School of Hygiene & Tropical Medicine (LSHTM).
Foundation funding: The Foundation is providing £165 K in support, together with co-funding from the European Union FP7 program through its COFUND scheme.
GSK’s contribution: GSK is providing expertise and know-how on high throughput screening and post-screening processes, as well as access to key facilities to set-up and perform this work. GSK is providing access to a wider chemical diversity for screening (chemical libraries) and to information about the parasitological and toxicological profile of the promising molecules identified.
Project Description: David Baker’s laboratory and collaborators have demonstrated in recent years that the malaria parasite cGMP-dependent protein kinases (PKG) has essential roles during a number of stages of its complex life cycle. Specific PKG inhibitors prevent blood stage parasite development by blocking both merozoite egress and invasion. They also block transformation of gametocytes into gametes, ookinete motility in the mosquito as well as late liver stage development. A recent drug discovery partnership between the LSHTM and MRC Technology generated highly potent and selective inhibitors of the malaria parasite PKG with excellent activity against both replicative and transmissible stages. The compounds were active in vivo via the oral route and one of them cleared P. falciparum infection in the GSK SCID model. This project will screen GSK compound libraries to identify new inhibitor scaffolds that target the malaria parasite PKG enzyme with the final aim of developing a drug that can be used to both treat malaria and block transmission.
National Institute of Blood Transfusion & INSERM - BlockBackMalaria” - Block rings and gametocytes in the spleen to block Malaria (Europe)
Start : July 2015 | Status : Complete
The scientists: Julien Duez will focus his research on the discovery of new drugs against Plasmodium falciparum, through a project titled "BlockBackMalaria”. The objective is to block early asexual stages (rings) and mature sexual stages (stage 5 gametocytes) in the spleen to cure clinical attacks and interrupt transmission. Julien is a Postdoctoral Researcher affiliated to National Institute for Blood Transfusion (INTS) and INSERM in Paris, under the mentorship of Pierre Buffet, PI of the project. Julien is specialized in biology-medicinal chemistry, with a 3-year experience in malaria drug screening. Another post-doctoral student and an experienced graduate investigator will soon join the team.
The sponsor: The French National Institute for Blood Transfusion (INTS) is a public benefit corporation hosting scientific, training and reference activities in a bid to improve transfusion safety and optimize transfusion practices. At INTS, the team works on erythrocyte biomechanics under normal or physiopathological conditions (ie. malaria or transfusion) in relation to human spleen filtering properties.
Founded in 1964, the French National Institute of Health and Medical Research (Inserm) is a public scientific and technological institute which operates under the joint authority of the French Ministry of Health and French Ministry of Research. Inserm has forged close partnerships with others public and private research establishments, such as INTS.
Foundation funding: The Foundation is providing £99,120 in support.
GSK’s contribution: GSK will allocate in-kind contribution to the project, including scientific expertise in malaria and HTS screenings as well as access to the GSK´s collection of compounds.
Project Description: This proposal is a continuation of a project funded by the Bill & Melinda Gates Foundation. The project team has established a screening and post-screening process based on a filtration device that replicates the mechanical sensing of circulating red blood cells (RBC) by the human spleen. Active compounds are expected to stiffen and induce the mechanical retention of Plasmodium falciparum-infected RBC in the spleen, thereby triggering their rapid clearance from the circulation. Using the RBC filtration system adapted to microplates, a candidate compound (calyculin) has been shown to induce the mechanical retention of 80-90% of mature gametocytes at concentrations lower than those affecting their viability. Calyculin-stiffened mature gametocytes were also held into spleno-mimetic microfluidic chips and were cleared from the circulation of macrophage depleted mice as rapidly as heat-stiffened control uninfected RBC, validating the outcomes of the microsphiltration assay.This project will extend the screening to asexual stages (circulating rings) and increase throughput to screen larger libraries on blood stages and mature gametocytes.
London School of Hygiene and Tropical Medicine - Optimization of imidazopyridine and thiazole scaffolds targeting plasmodial kinases to generate a fast killing compound to treat malaria infection and block transmission (Europe)
Start : January 2017 | Status : Active
The scientists: Dr Alexios Matralis and Adnan Malik will work in the optimization of imidazopyridine and thiazole scaffolds targeting plasmodial kinases. Both researchers are medicinal/organic chemists with post-doctoral experience. Their main role will be the design, synthesis and characterization of the new compounds as well as the proposal of new ideas based on the acquired knowledge.
The sponsor: London School of Hygiene & Tropical Medicine
Foundation funding: The Foundation is providing £132,140 in support.
GSK’s contribution: GSK will contribute its experience in phenotypic programs, medchem expertise, parasitology, in vitro assays, safety, and its in vivo humanized mouse model.
Project Description: Starting from a set of compounds prepared by D. Baker’s group that showed activity in GSK phenotypic and dual gamete formation assays on top of its activity against P. falciparum cGMP-dependent protein kinase (PfPKG), this open lab will focus on improve the physchem profile of these families, increase their potency in the phenotypic/dual gamete formation assays, abolish toxicity issues, and gain knowledge of their in vitro killing profile in order to focus only in fast killing compounds. The aim of the project is to deliver compounds active in vivo in the P. falciparum mouse model, with physicochemical properties that allow developability and adequate safety profile.
University of Georgia - Rapid selection of in vivo active anti-Trypanosoma cruzi compounds (America)
Start : July 2016 | Status : Completed
The scientists: Dr. Alba Gigante is an organic/ medicinal chemist by training, with experience working in neglected diseases. Currently she is a Postdoctoral Researcher working with Prof. Rick Tarleton from the University of Georgia. Her primary role in this project is to identify novel phenotypic leads against Trypanosoma cruzi from the TCAKS_CHAGAS set (Tres Cantos Anti Kinetoplastid Set). During her stay in Tres Cantos she will perform analog searches within GSK library for the in vivo active hits as well as the design of convergent synthetic routes for further SAR enrichment.
The sponsor: University of Georgia
Foundation funding: The Foundation is providing £189,705 in support.
GSK’s contribution:GSK will contribute with solid availability for compounds in the TCAKS_CHAGAS set (Tres Cantos Anti Kinetoplastid Set) as well as analogue searching within the GSK collection. GSK will contribute in-kind its drug discovery expertise supporting the design of new analogues as well as completing preliminary compound profiling (in vitro T.cruzi, in vitro ADMET)
Project Description: T. cruzi is a protozoan parasite that causes Chagas disease, the highest impact infectious disease in Latin America. Previous work at Tres Cantos has identified a total of 222 small molecule prioritized according to their potency against T.cruzi, cytotoxicity, and physico-chemical properties, called TCAKS-Chagas. The purpose of this project is to determine which among these prioritized in vitro-active compounds also has substantial in vivo activity on T. cruzi, and thus promise as a hit for lead compound development.
The investigators from University of Georgia, led by Prof. Rick L. Tarleton, have developed a facile and rapid assay that makes use of transgenic T. cruzi lines expressing fluorescent proteins, which allows imaging the establishment and expansion of these tagged parasites after a single administration of compound, and hence determine in vivo efficacy of a number of compounds (up to 30 at a time) in < 1 week. This rapid in vivo assay seems to be an excellent predictor of long-term efficacy and is thus a potent screening method for selection of candidates for subsequent studies.
Structural Genomics Consortium - Identification of small molecule inhibitors targeting plasmodium methyltransferase SET1 and elongation factor 2 (Europe)
Start : March 2016 | Status : Completed
The scientists: Dr. Cynthia Tallant is a Postdoctoral Researcher in the Chemical Biology Unit at the Structural Genomics Consortium (SGC), working under the supervision of Dr. Kilian Huber and Dr. Raymond Hui. She has a PhD in Structural Biology and Enzyme Kinetics and several years of experience as a PostDoc in these areas
The sponsor: The Structural Genomics Consortium, Structural and Chemical Parasitology lab (Oxford and Toronto).
Foundation funding: The Foundation is providing £160,915 in support, together with co-funding from the European Union FP7 program through its COFUND scheme
GSK’s contribution: GSK is providing scientific expertise in screening, enzymology, medicinal chemistry, in vitro parasite culture as well as access to Biosafety Level 3 facilities and to GSK´s collection of proprietary compounds.
Project Description: The focus of the project will be the exploration of new antimalarial targets involved in parasite transcriptional regulation, such as the histone methyltransferase (HMT) SET1, and protein biosynthesis pathways controlled by the ribosomal translation elongation factor 2 (eEF2).
A number of histone methyltransferase inhibitors have been shown to inhibit parasite growth in the intraerythrocytic cycle in both P. falciparum and P. vivax ex vivo experiments. Concomitantly, these same compounds were shown to reduce H3K4me3 methylation levels in parasites. Additional genetic studies in P. falciparum showed that some of these genes are essential for the parasite in the asexual blood stage. Recently, a novel antimalarial compound DDD107498 has been discovered and publicly discosed. This compound has excellent drug-like properties and exhibits a potent activity profile against multiple life-cycle stages of the parasite. Its molecular target has been identified as the translation elongation factor 2 (eEF2) using whole genome sequencing of resistant cell lines treated with DDD107498. This finding nominates PfEF2 as a novel antimalarial target. Together, the proposal aims to identify chemically diverse compounds targeting these two classes of enzymes, with activity against resistant mutants and inert to the human orthologues.
Biomedical Primate Research Centre- Optimization of hepatocyte culture to support drug screening for malaria hypnozoites (Europe)
Start : May 2017 | Status : Completed
The scientists: Anke Harupa – Lars Vermaat
The sponsor: Biomedical Primate Research Centre
Foundation funding: The Foundation is providing £141,552 in support
GSK’s contribution: We envisage GSK’s contribution in the field of hepatocyte culture, which will be of great value to the project. The Open Lab scientist will perform part of the hepatocyte culture optimization at GSK facilities, GSK will provide consumables for these periods in kind as well as mentoring from experienced researchers.
Project Description: The BPRC P. cynomolgi in vitro liver stage drug assay, enabling drug screening on developing- and dormant liver stages (hypnozoites), may be biased towards prophylactic compound activity, rather than radical curative activity. The assay is performed with primary rhesus monkey hepatocytes and drug exposure from day 0 to 6 days post sporozoite infection. We are currently developing an assay that may be more predictive for radical curative activity, by applying compound exposure from day 5 to 9 post infection. Primaquine (PQ), the only positive control with known radical curative activity in vivo, has variable activity in the standard assay and no activity in the radical cure type assay. Thus, we are lacking a positive control in the assay. As PQ needs to be metabolized to display anti-hypnozoite activity, it is likely that declining metabolic activity over time of the primary hepatocytes causes this variable activity in the standard assay and absence of activity in the radical cure type assay. We plan to address this by first fully characterizing hepatocytes during culture and in the liver prior to isolation. This includes typical hepatocyte markers as well as the metabolism capacity. We will then apply alternative culture methods and monitor PQ metabolism over time. Finally, we will monitor parasite invasion and growth and PQ anti-parasite activity over time, and adapt culture conditions further to arrive at an optimal radical cure type assay. Once the radical cure assay is optimized, a set of compounds will be screened, using PQ as the positive control, aiming to identify novel compounds with radical cure activity.
Utrecht University - Attacking Shigella by blocking its disease causing Toxin (Europe)
Start : October 2017 | Status : Completed
The scientists: Jie Shi – Torben Heise
The sponsor: University of Utrecht
Foundation funding: The Foundation is providing £152,256 in support.
- Use of premises (space), associated site costs and shared service support
- Lab supplies at GSK
- Pre-clinical development services (in vivo studies, Chem Dev, Pharm Dev)
- Access and support from a “GSK mentor” throughout the duration of the project
- Support from other scientists as project needs.
Project Description: Our approach towards Shigella involves the Shiga toxin as its target. This toxin causes serious disease,and is clearly on the rise in the dominant Shigella species in the developing world. It is an AB5 toxin that binds to multiple copies of a carbohydrate moiety expressed on the cell surface. We intend to design and synthesize the optimal binding moieties for toxin binding. These designs are based on our previously successful rigid spacer design for bridging binding sites and on our approach to inhibit the related Cholera AB5 toxin at picomolar concentrations. The focus is on intercepting the toxin in the blood stream. The Shiga toxin is an excellent target as it should be amenable to very potent inhibition and a demonstration of in vivo susceptibility has already been made. We intend to design and synthesize the compounds in Utrecht (UU) and explore their potency and activity at OL.
University of Melbourne - High throughput screening to identify selective proteasome inhibitors as new antimalarials with a novel mode of action (Oceanía)
Start : May 2017 | Status: Completed (31/01/2021)
The scientists: Dr. Stanley Xie is a postdoctoral researcher at the University of Melbourne, working under the supervision of Dr. Leann Tilley. He has extensive experience studying the P. falciparum proteasome and the mechanisms of action of and resistance to artemisinins. He will focus his research on identification and characterization ofnew hits acting through the P. falciparum proteasome.
The sponsor: University of Melbourne
Foundation funding: The Foundation is providing £198.239 in support.
GSK’s contribution: GSK will support the project with its enzymology and high throughput screening platforms and contribute with its past experience working on the P. falciparum Ubiquitin Proteasome System. Additionally, GSK will also provide access to Biosafety Level 3 facilities and to GSK´s collection of proprietary compounds.
Project Description: Current antimalarial control is highly dependent on Artemisinin-based Combination Therapies (ACTs), which makes the emergence of artemisinin (ART) resistance extremely concerning. This situation highlights the need to identify new drugs targeting different mechanisms in the parasite. The proteasome is a validated target for malaria. Inhibitors of the proteasome show parasiticidal activity against both ART sensitive and resistant parasites, and are active both against sexual and asexual intraerythroctyic stages, as well as liver stages. Moreover, the Leann Tilley lab has demonstrated that inhibitors of the proteasome strongly synergize ART-mediated killing of P. falciparum, being also suitable for combination therapies.
The objective of this Open Lab project is to undertake a screening campaign to identify P. falciparum-specific proteasome inhibitors, thereby avoiding any toxicity associated with inhibition of the human proteasome. An extensive compound characterization will be performed, determining the parasitological profile and the mechanism of action applying tools developed in parallel during the project.
University of Alabama at Birmingham - Self-poisoning of Mycobacterium tuberculosis by inhibiting siderophore secretion (America)
Start : July 2016 | Status: Completed (31/01/2021)
The scientists: Dr. Avishek Mitra, Bjorn Sunde and Prof. Michael Niederweis will focus their research on the identification of small molecules that kill Mycobacterium tuberculosis by inhibiting siderophore efflux. Dr. Mitra is a postdoctoral researcher working on iron acquisition by M. tuberculosis in the laboratory of Prof. Niederweis in the Department of Microbiology at the University of Alabama at Birmingham. Bjorn Sunde is a research assistant with experience in performing high-throughput screening assays in Biosafety Level 3 laboratories.
The sponsor:University of Alabama at Birmingham, Department of Microbiology
Foundation funding: The Foundation is providing £263,119 in support.
GSK’s contribution: GSK will provide access to biosafety level 3 and high-throughput screening facilities, microbiology and drug discovery expertise as well as full access to antimycobacterial compound sets.
Project Description: Iron is an essential nutrient for M. tuberculosis which can acquire iron from heme and from its siderophores, mycobactin and carboxymycobactin. This project is based on the surprising finding that blocking siderophore secretion reduces the virulence of Mtb in mice by 10,000-fold. This is one of the strongest virulence defects observed for any Mtb mutant, probably due to the intracellular accumulation of siderophores. Externally added siderophores accumulate in the Mtb secretion mutant and are toxic at submicromolar concentrations. Importantly, this toxicity cannot be overcome by other iron sources such as heme in contrast to Mtb mutants deficient in siderophore biosynthesis. Since siderophore secretion spans both membranes, inhibitors might target this pathway from the outside of the cell and, thereby, might avoid the outer membrane permeability barrier of Mtb.
We have developed a high-throughput screening assay that has identified inhibitors of Mtb whose activity depends on siderophores. These compounds are not detected in whole cell screens under standard conditions. Thus, siderophore secretion appears to be a valuable target for novel TB drugs that will be exploited in this project.
University of Washington - High Throughput Screening for Inhibitors of Shigella Virulence Determinants (America)
Start : June 2019 | Status : Completed (09/11/2020)
The scientists: Mayumi Holly
The sponsor: University of Washington
Foundation funding: The Foundation is providing £166,037 in support.
GSK’s contribution: Technical assistance with the inhibitor screen including help with instruments and software. Access to GSK’s small molecule libraries. Extensive communication and advice regarding screen design, execution, troubleshooting, and compound identification.
Project Description: The primary goal of this proposed project is to test the hypothesis that small molecule inhibitors of Shigella transcription factors can promote the rapid resolution of infection. Previously, data collected from an in vivo transposon library screen (TN-Seq) using a guinea pig model of shigellosis was performed to provide a global view of genes and pathways that are critical for Shigella to survive and compete within the host. Disrupting the expression of these crucial genes and pathways with small molecule inhibitors is expected to result in severe defects in Shigella’s ability to colonize the host and cause disease. The proposed project will use high throughput assays to screen compound libraries for inhibition of pathways deemed to be essential for Shigella to survive in the host. Identified hits will be validated and tested for their capacity to functionally alter the course of Shigella infection using established in vivo models. If successful, this strategy could act as a blueprint for developing new drugs that target essential survival pathways in microorganisms, leading to an entire new class of treatments against infectious diseases.
IBR-CONICET_UNR Instituto de Biología Molecular y Celular de Rosario - Trypanosoma cruzi bromodomains: druggable readers to look out! (America)
Start : March 2019 | Status : Completed (31/12/2020)
The scientists: Luis Emilio Tavernelli
The sponsor: IBR-CONICET_UNR Instituto de Biología Molecular y Celular de Rosario
Foundation funding: The Foundation is providing £101,055 in support
GSK’s contribution: GSK will give us access to a library of potential bromodomain inhibitors, as well to humans BRD proteins. On the other hand, GSK will let us introduce us in the field of high/medium throughput screening in which we lack expertise.
Project Description: The discovery of new therapeutic options against Trypanosoma cruzi, the causative agent of Chagas disease stands as a fundamental need, since available drugs have significant toxic side effects and a variable efficacy against the life-threatening symptomatic chronic stage of the disease. Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests their role in interpreting the histone code. However, protein acetylation is not a phenomenon restricted to the nuclear proteins. Bromodomain-containing proteins are often found as components of larger protein complexes with roles in fundamental cellular process including transcription, cell cycle regulation, among others. In 2010 two BET bromodomains ligands were described demonstrating that small molecules could inhibit the bromodomain-acetyl-lysine interaction. These molecules display strong phenotypic effects in a number of cell lines and affect a range of cancers in vivo. Recent reports showed that bromodomain inhibitors affect T. cruzi viability and deregulate the expression of stage-specific proteins in T. brucei. The overall objective of this project is to search for bromodomain inhibitors in T. cruzi, by assaying essentials bromodomains previously established in a collaborative GSK-sponsored research project between Esteban Serra’s and Roberto Docampo’s labs. From this project three bromodomains from T. cruzi were selected as putative targets against Chagas disease.
Research Agency of Aragon (ARAID) & University of Zaragoza (UNIZAR)- Predicting optimal dosing schedules and clinical outcomes of beta‐lactams for TB therapy using PKPD and mechanistic models Carbapenem vs. cephem: the beta‐lactam paradigm (Europe)
Start : April 2018 | Status : Completed (31/12/2020)
The scientists: Santiago Ramón - María Pilar Arenaz
The sponsor: Research Agency of Aragon (ARAID) & University of Zaragoza (UNIZAR)
Foundation funding: The Foundation is providing £141,500 in support
GSK’s contribution: GSK’s in kind contributions would be critical for the following: (i) Access to time-lapse microscopy and micro-pumping system to mimic PK profiles; (ii) imaging and analytical modeling software and skills; (iii) access to clinical data for modeling. In addition, based on previous experience (RIFACEPH project), the excellent scientific and personal support provided by GSK scientists would greatly facilitate the successful outcome of this proposal.
Project Description: This proposal aligns and complements with current clinical trials now being explored by GSK DDW clinical partners. It also comes with additional funding that the applicant, Dr. Ramón-García, recently secured from the European Community for a 2-year project to be performed at GSK DDW.
Carbapenems and cephems are beta-lactam (BLMs) antibiotics with different anti-tuberculosis (TB) killing properties and phenotypic responses that might affect therapy design for optimal clinical outcomes (Figure 1). Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of BLMs alone and in combination with synergistic partners is critical if they are to be used for TB therapy (Figure 2). Similarly, the molecular determinants underlying synergistic interactions of BLMs with synergistic partner drugs are currently unknown. Elucidating the synergistic mode of action of such combinations will allow the design of novel strategies for TB therapy and help counteract the emergence of future resistance.
To answer these questions, time-lapse microscopy, in vitro microbiology assays and transcriptomic studies will be leveraged to provide high quality molecular and pre-clinical data that, through mathematical PKPD modeling based on completed and ongoing GSK DDW BLM-containing TB clinical trials, will inform the design of future human combination trials with BLM components.Campylobacter spp. and Salmonella spp.). Through this Open Lab project, this characteristic will be exploited for high-throughput screens against Shigella spp. and other enteric bacteria.
University of Georgia + Bioaster- Chagas AABLO (Chagas AcylAminoBenzothiazol Lead Optimization) (Europe)
Start : January 2018 | Status : Completed (31/12/2020)
The scientists: Charlotte Fleau
The sponsor: University of Georgia + Bioaster
Foundation funding: The Foundation is providing £159,226 in support
GSK’s contribution: Chemistry labs for synthesis, purification, structure analysis. Full Profiling of Development pre-Candidate (ADMET2 and early toxicology).
Project Description: T. cruzi is a protozoan parasite that causes Chagas disease, the highest impact infectious disease in Latin America. Although the host immune response is highly effective at controlling T. cruzi, the infection persists in most infected hosts. Previous work between our groups at The University of Georgia (UGA), Sanofi and BIOASTER has identified several Acyl-AminoBenzothiazol (AAB) hits with potent in vitro and in vivo toxicity for T. cruzi. These related hits came from an initial in vitro screen of a ~300,000 small molecule library by the Broad Institute (Pubchem AID: 1885); 171 of the ~3500 in hits with in vitro activity were selected for in vivo screening based upon druglikeness, potential for oral delivery and ease of synthesis and novelty. In a rapid in vivo efficacy assay, 5 of the 171 compounds showed strong activity – 3 of those 5 were in this AAB group. Subsequent in vitro SAR of 240 analogues revealed 3 AAB compounds with IC50 of < 80 nM and identified the steps needed to optimize this compound class. Herein we describe the med chem plan for this optimization as well as for identification of the mechanism of action of these compounds. Paired with our unparalleled combination of in vitro and in vivo screening assays, and the prior evidence of in vivo efficacy of this compound class, we have an excellent opportunity to identify one or more compounds capable of providing parasitological cure.