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PMID: 19620707 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Vinyl sulfones as antiparasitic agents and a structural basis for drug design.

The Journal of biological chemistry ·Vol. 284 ·No. 38 ·2009-09-18 ·Pages 25697-703

Kerr ID, Lee JH, Farady CJ, Marion R, Rickert M, Sajid M, Pandey KC, Caffrey CR, Legac J, Hansell E, McKerrow JH, Craik CS, Rosenthal PJ, Brinen LS

Abstract

Cysteine proteases of the papain superfamily are implicated in a number of cellular processes and are important virulence factors in the pathogenesis of parasitic disease. These enzymes have therefore emerged as promising targets for antiparasitic drugs. We report the crystal structures of three major parasite cysteine proteases, cruzain, falcipain-3, and the first reported structure of rhodesain, in complex with a class of potent, small molecule, cysteine protease inhibitors, the vinyl sulfones. These data, in conjunction with comparative inhibition kinetics, provide insight into the molecular mechanisms that drive cysteine protease inhibition by vinyl sulfones, the binding specificity of these important proteases and the potential of vinyl sulfones as antiparasitic drugs.

MeSH Terms
Animals Antiparasitic Agents/chemistry,therapeutic use Chagas Disease/drug therapy,enzymology Crystallography, X-Ray Cysteine Endopeptidases/chemistry Drug Design Kinetics Malaria, Falciparum/drug therapy,enzymology Plasmodium falciparum/enzymology Protease Inhibitors/chemistry,therapeutic use Protein Binding Protein Structure, Tertiary Protozoan Proteins/antagonists & inhibitors,chemistry Sulfones/chemistry,therapeutic use Trypanosoma brucei brucei/enzymology Trypanosoma cruzi/enzymology Trypanosomiasis, African/drug therapy,enzymology
Chemicals
Antiparasitic Agents Protease Inhibitors Protozoan Proteins Sulfones divinyl sulfone Cysteine Endopeptidases cruzain, Trypanosoma cruzi falcipain 3 rhodesain
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Kerr Iain D
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158-2550, USA.
Lee Ji H
Farady Christopher J
Marion Rachael
Rickert Mathias
Sajid Mohammed
Pandey Kailash C
Caffrey Conor R
Legac Jennifer
Hansell Elizabeth
McKerrow James H
Craik Charles S
Rosenthal Philip J
Brinen Linda S
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M109.014340
Published
2009-09-18
Epub
2009-00-20
Pages
25697-703
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2757971
Subset
IM
Grants
NIAID NIH HHS · P01 AI035707 · United States
NIAID NIH HHS · R56 AI035800 · United States
NIAID NIH HHS · AI35800 · United States
NIAID NIH HHS · R29 AI035800 · United States
NIAID NIH HHS · AI35707 · United States
NIAID NIH HHS · R01 AI035800 · United States
Databases
PDB
2OZ2, 2P7U, 3BWK
External Links
PubMed source DOI: 10.1074/jbc.M109.014340 PMC Full Text View journal details
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