Ten major pathogenic protozoa form a serious threat to the well-being of humankind. There is a desperate need for new medicines for treating infected patients and for use as prophylaxis. The proposed interdisciplinary MSGPP Program Project will accelerate anti-protozoan drug development by: (i) Analyzing the genomes sequences from the targeted protozoa for suitable MSGPP protein targets from a functional and ligand perspective; (ii) Expressing, crystallizing and determining three-dimensional structures of the selected crucial proteins, focusing on complexes with small molecule ligands; (iii) Applying computational processes to these structures to predict new ligands targeting key sites of the selected proteins; (iv) Discovering in solution small molecule ligands binding to target proteins; (v) Using such ligands for the development of new leads and drug candidates, in collaboration with interested institutions. Protein targets will be selected from the following pathogenic protozoa: Plasmodium falciparum, Plasmodium vivax, Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, Leishmania infantum, Entamoeba histolytica, Giardia lamblia, Cryptosporidium parvum, and Toxoplasma gondii. All of these organisms are the subject of ongoing or completed Genome Sequencing Projects. The last four pathogens are BIAID Category B Biodefense organisms. In the course of the three years duration of this Program Project, we estimate to obtain 428 soluble protein variants, representing 183 distinct target proteins, which will result in tree-dimensional structures of around 50 target proteins, plus about 250 target protein structures with ligands bound to them. This MSGPP Program Project includes four tightly integrated Projects and two Cores. We have a unique prior experience, as members of the Structural Genomics of Pathogenic Protozoa (SGPP) consortium, to perform the proposed research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI067921-02
Application #
7216835
Study Section
Special Emphasis Panel (ZAI1-AR-M (S1))
Program Officer
Rogers, Martin J
Project Start
2006-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$2,248,842
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
PedrĂ³-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
Koh, Cho Yeow; Kim, Jessica E; Napoli, Alberto J et al. (2013) Crystal structures of Plasmodium falciparum cytosolic tryptophanyl-tRNA synthetase and its potential as a target for structure-guided drug design. Mol Biochem Parasitol 189:26-32
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
Larson, Eric T; Ojo, Kayode K; Murphy, Ryan C et al. (2012) Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1. J Med Chem 55:2803-10
Koh, Cho Yeow; Kim, Jessica E; Shibata, Sayaka et al. (2012) Distinct states of methionyl-tRNA synthetase indicate inhibitor binding by conformational selection. Structure 20:1681-91
Zucker, Frank H; Kim, Hae Young; Merritt, Ethan A (2012) PROSPERO: online prediction of crystallographic success from experimental results and sequence. J Appl Crystallogr 45:598-602
Johnson, Steven M; Murphy, Ryan C; Geiger, Jennifer A et al. (2012) Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity. J Med Chem 55:2416-26
Larson, Eric T; Kim, Jessica E; Napuli, Alberto J et al. (2012) Structure of the prolyl-tRNA synthetase from the eukaryotic pathogen Giardia lamblia. Acta Crystallogr D Biol Crystallogr 68:1194-200
Shibata, Sayaka; Zhang, Zhongsheng; Korotkov, Konstantin V et al. (2011) Screening a fragment cocktail library using ultrafiltration. Anal Bioanal Chem 401:1585-91

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