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