Principal Investigator (PI)
Global Network for Neglected Tropical Diseases- Durham University & Institut Pasteur Montevideo
The Foundation is providing £301,151 in support.
Edubiel Alpizar-Sosa at Durham University
Carlos Sanz-Rodriquez at Institut Pasteur Montevideo
Whilst the MRC GCRF Global Network for NTDs, and partners at the Universities of Newcastle and Glasgow, provide financial resource, expertise, equipment and infrastructure support, the project is completely reliant on GSK to supply adequate quantities of the compounds which they have already triaged and selected for analyses.
Beyond this physical contribution, GSK expertise will be vital through WP1 and WP2 to ensure focus remains on research that has the potential to impact on cutaneous and visceral leishmaniasis and Chagas disease. In particular, as targets are identified they must be thoroughly evaluated for their ‘druggable’ potential – host similarity, tractability for further study (e.g. structural determination), availability of experimental ligand binders etc. Further engagement could include the accelerated development and analyses (e.g. in vivo) of compounds for which a mode of action is identified. This would require GSK-wide expertise in medical chemistry, pharmaceutics and animal models, and could lead towards rapid clinical evaluation.
Finally, and importantly, in the final 10 months of the project, the assigned PDRAs and PhD will be guided and mentored by GSK colleagues to facilitate both the assessment of the compounds for hit-to-lead programmes and the formatting of protein drug targets into HTS assay platforms for further analyses and discovery.
In summary, by working with GSK we will ensure that high level industrial standards are maintained and outcomes maximised.
Caused by the insect-borne kinetoplastid protozoa Leishmania species and Trypanosoma cruzi, the Neglected Tropical Diseases leishmaniasis and Chagas disease represent a major and increasing threat to the health of individuals in the developing world. In the absence of vaccines, drugs are the mainstay of treatment and control. However, these are limited in number and efficacy, and have significant problems in administration and toxicity. To develop new therapies it is necessary to identify essential parasitic processes (drug targets) and compounds that disrupt these.
The start point for this project are 15 compounds identified by GSK as anti-kinetoplastid and having properties favourable for development, but for which the mode of action is unknown. This lack of knowledge hampers understanding and development, and within this research proposal we will apply advanced molecular-genetic, biophysical and analytical technologies to reveal new modalities for drug discovery.
By engaging in a unique transnational co-fund collaborative arrangement, GSK Tres Cantos and the Durham-led MRC GCRF Global Network for Neglected Tropical Diseases will undertake a milestone-based programme designed to maximise outputs and impact. Analysing in vitro evolution of resistance, coupled with whole genome sequencing and modern gene editing validation tools, will provide preliminary evidence of mode of action/resistance. Subsequently, leading metabolomic, lipidomic and thermal proteomic technologies will be employed alongside advanced molecular-genetic tools to provide full target validation. Importantly, these drug targets will also have available drug-like inhibitors. Assessing these targets and formatting them into HTS-ready assay platforms, alongside hit-to-lead evaluation of the small molecule inhibitors, will be the primer for future drug discovery initiatives for leishmaniasis and Chagas disease