Developing methionyl tRNA synthetase inhibitors as therapeutics for Chagas disease

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Project Summary In this project, inhibitors of the enzyme methionyl-tRNA synthetase from the protozoan parasite Trypanosoma cruzi will be optimized to develop new drug candidates for Chagas disease. The available treatments for Chagas disease are highly toxic and not fully efficacious, especially for the chronic stage. They need to be replaced with safer and more effective drugs to treat the millions of people, mainly in Latin America, afflicted by Chagas disease. The proposed research is based on the strong preliminary data of methionyl-tRNA synthetase inhibitors from multiple chemical scaffolds showing nanomolar potency against T. cruzi cells, low toxicity to mammalian cells, oral availability, and potent activity in murine infection models. We have chosen two chemical scaffolds for lead optimization. Pre-defined criteria will be used to advance compounds through a rigorous screening cascade, and the results will continually be fed back into the iterative design and synthesis process. The goal for this project is to identify one preclinical candidate and at least one backup compound that are ready for comprehensive GLP preclinical pharmacology and toxicology studies for further development.