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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Barros-Álvarez, Ximena; Turley, Stewart; Ranade, Ranae M et al. (2018) The crystal structure of the drug target Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with a catalytic intermediate. Acta Crystallogr F Struct Biol Commun 74:245-254
Devine, William G; Diaz-Gonzalez, Rosario; Ceballos-Perez, Gloria et al. (2017) From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis. ACS Infect Dis 3:225-236
Huang, Wenlin; Zhang, Zhongsheng; Ranade, Ranae M et al. (2017) Optimization of a binding fragment targeting the ""enlarged methionine pocket"" leads to potent Trypanosoma brucei methionyl-tRNA synthetase inhibitors. Bioorg Med Chem Lett 27:2702-2707
Faghih, Omeed; Zhang, Zhongsheng; Ranade, Ranae M et al. (2017) Development of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram-Positive Bacterial Infections. Antimicrob Agents Chemother 61:
Barros-Álvarez, Ximena; Kerchner, Keshia M; Koh, Cho Yeow et al. (2017) Leishmania donovani tyrosyl-tRNA synthetase structure in complex with a tyrosyl adenylate analog and comparisons with human and protozoan counterparts. Biochimie 138:124-136
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
Khare, Shilpi; Nagle, Advait S; Biggart, Agnes et al. (2016) Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. Nature 537:229-233
Huang, Wenlin; Hulverson, Matthew A; Zhang, Zhongsheng et al. (2016) 5-Aminopyrazole-4-carboxamide analogues are selective inhibitors of Plasmodium falciparum microgametocyte exflagellation and potential malaria transmission blocking agents. Bioorg Med Chem Lett 26:5487-5491
Ojo, Kayode K; Dangoudoubiyam, Sriveny; Verma, Shiv K et al. (2016) Selective inhibition of Sarcocystis neurona calcium-dependent protein kinase 1 for equine protozoal myeloencephalitis therapy. Int J Parasitol 46:871-880
Ojo, Kayode K; Ranade, Ranae M; Zhang, Zhongsheng et al. (2016) Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis. PLoS One 11:e0160350

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