The goal of this project is to provide detailed atomic-level understanding of the structural determinants that affect selective and potent inhibition of the activity of cysteine protease involved in parasitic infection. The causative agents of Chagas' disease, African sleeping sickness, malaria and leishmaniasis (Trypanosoma cruzi, Trypanosoma brucei, Plasmodium falciparum and several Leishmania species, respectively) each contain cysteine proteases that are critical to the life cycles or the organisms. These proteases have been identified and biochemically characterized. In collaboration with William Roush's synthetic chemistry group, the chemical, electrostatic and steric topology of these cysteine proteases will be mapped via high resolution X-ray crystallographic structures of the enzymes bound to several series of small molecule synthetic inhibitor. Macromolecular endogenous inhibitors of the proteases will also be studied in complex with the enzymes in order to detail extended modes of recognition and the impact of allosteric effects. As structural information has been the basis for numerous advances in the development of new therapeutics in the last 25 years, insights obtained from both small and macromolecular complex structures will be used as starting points for next cycles of rational design of inhibitors. This work will be done in collaboration with the Roush group as well as theFred Cohen/Andrej Sali computational cores.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI035707-10
Application #
6816896
Study Section
Special Emphasis Panel (ZAI1-AC-M (J2))
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2004-06-18
Budget End
2005-05-31
Support Year
10
Fiscal Year
2004
Total Cost
$100,064
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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