Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of
Plasmodium falciparum
by Peptidyl Vinyl Sulfones
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Published:2003-01
Issue:1
Volume:47
Page:154-160
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ISSN:0066-4804
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Container-title:Antimicrobial Agents and Chemotherapy
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language:en
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Short-container-title:Antimicrob Agents Chemother
Author:
Shenai Bhaskar R.1, Lee Belinda J.1, Alvarez-Hernandez Alejandro2, Chong Pek Y.2, Emal Cory D.2, Neitz R. Jeffrey2, Roush William R.2, Rosenthal Philip J.1
Affiliation:
1. Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 2. Department of Chemistry, University of Michigan, Ann Arbor, Michigan
Abstract
ABSTRACT
The
Plasmodium falciparum
cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of
P. falciparum
in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited
P. falciparum
development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P
2
leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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