In this proposal several series of potent inhibitors of the enzyme methionyl-tRNA synthetase from the protozoan parasite Trypanosoma brucei will be optimized with long term goals to arrive at new therapeutics for treating human African trypanosomiasis. The research will be carried out by a highly experienced team formed by scientists at the University of Washington and PATH with expertise covering: structure-based drug design, medicinal chemistry, parasitology, pharmacology, toxicology, and preclinical testing. The proposed research is based on the strong progress made during the current funding period where multiple series of T. brucei methionyl-tRNA synthetase inhibitors were obtained that showed nanomolar potency against parasite cells, low toxicity to mammalian cells, oral and CNS availability, and efficacy in murine infection models. The proposed work will have four specific aims. 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 preclinical candidate and one to two backup compounds 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, orally and CNS available, low cost, and less toxic drugs for treating the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI097177-06
Application #
9217544
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
O'Neil, Michael T
Project Start
2012-05-01
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
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:
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
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
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
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; 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; 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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