Principal Investigator (PI)
The Foundation is providing £57,800 in support.
Vaibhav Mehta - Stephan Zimmermann
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.
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.