In this proposal structure-based drug design approaches will be used to optimize a series of selective inhibitors of the enzyme methionyl tRNA synthetase from the protozoan parasite Trypanosoma brucei. The long term goal is to arrive at new therapeutics for treating human African trypanosomiasis caused by T. brucei infection. The research will be carried out by a highly experienced research team at the University of Washington consisting of four scientists: Dr. Fan (chemistry), Dr. Buckner (pharmacology and parasitology), Dr. Gelb (pharmacology and chemistry), and Dr. Verlinde (structure-based drug design). The proposed research is based on several key preliminary findings. These include: genetic and chemical validation of methionyl tRNA synthetase as a drug target against T. brucei infection;identification of compounds that inhibit parasite growth a high-nanomolar concentrations;discovery of a molecular scaffold that demonstrates oral bioavailability and excellent membrane permeability with potentially CNS penetration;and inhibitor-bound crystal structures of the target enzyme through collaboration with Dr. Hol at the University of Washington. The proposed work will have two specific aims.
One aim i s to use structure-based design to guide synthesis of next generation inhibitors of T. brucei methionyl tRNA synthetase with improved potency and metabolic stability while preserving selectivity and membrane permeability.
The second aim i s to use a set of well-established biological assays to evaluate the newly synthesized compounds in terms of efficacy, pharmacological properties, and toxicity. Pre-defined criteria will be used to pass or fail compounds coming to each biological test, and the results will continually be fed back into the iterative design process. Th potential for drug resistance will also be examined. The goal for this project is to identify one lead and one backup compound that are ready for comprehensive GLP preclinical pharmacology and toxicology studies for further development.

Public Health Relevance

Human African trypanosomiasis is a largely neglected parasitic disease most prevalent in sub-Saharan Africa and putting more than 60 million people at risk. This proposal directly addresses the need of more effective, low cost, and less toxic drugs for treating the disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
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Rogers, Martin J
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University of Washington
Schools of Medicine
United States
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Zhang, Zhongsheng; Koh, Cho Yeow; Ranade, Ranae M et al. (2016) 5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors. ACS Infect Dis 2:399-404
Huang, Wenlin; Zhang, Zhongsheng; Barros-Álvarez, Ximena et al. (2016) Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors. Eur J Med Chem 124:1081-1092
Koh, Cho Yeow; Siddaramaiah, Latha Kallur; Ranade, Ranae M et al. (2015) A binding hotspot in Trypanosoma cruzi histidyl-tRNA synthetase revealed by fragment-based crystallographic cocktail screens. Acta Crystallogr D Biol Crystallogr 71:1684-98
Pedró-Rosa, Laura; Buckner, Frederick S; Ranade, Ranae M et al. (2015) Identification of potent inhibitors of the Trypanosoma brucei methionyl-tRNA synthetase via high-throughput orthogonal screening. J Biomol Screen 20:122-30
Ranade, Ranae M; Zhang, Zhongsheng; Gillespie, J Robert et al. (2015) Inhibitors of methionyl-tRNA synthetase have potent activity against Giardia intestinalis trophozoites. Antimicrob Agents Chemother 59:7128-31
Koh, Cho Yeow; Kim, Jessica E; Wetzel, Allan B et al. (2014) Structures of Trypanosoma brucei methionyl-tRNA synthetase with urea-based inhibitors provide guidance for drug design against sleeping sickness. PLoS Negl Trop Dis 8:e2775
Ranade, Ranae M; Gillespie, J Robert; Shibata, Sayaka et al. (2013) Induced resistance to methionyl-tRNA synthetase inhibitors in Trypanosoma brucei is due to overexpression of the target. Antimicrob Agents Chemother 57:3021-8
Shibata, Sayaka; Gillespie, J Robert; Ranade, Ranae M et al. (2012) Urea-based inhibitors of Trypanosoma brucei methionyl-tRNA synthetase: selectivity and in vivo characterization. J Med Chem 55:6342-51