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  • Title: Macrocyclic inhibitors of HCV NS3 protease.
    Author: Venkatraman S, Njoroge FG.
    Journal: Expert Opin Ther Pat; 2009 Sep; 19(9):1277-303. PubMed ID: 19563268.
    Abstract:
    BACKGROUND: HCV NS3 is a serine protease that plays a pivotal role in catalyzing the cleavage of the single polyprotein encoded by HCV after infection of hepatocytes. Analysis of the X-ray crystal structure of the enzyme reveals a shallow catalytic site located on the surface of the protein, which has made development of inhibitors a formidable task. Attempts to discover leads by a traditional approach of screening of compound libraries have proved futile and, therefore, researchers have adopted a structure-based drug design. Analysis of the X-ray structure of NS3 protease reveals close proximity of S(1)-S(3) and S(2)-S(4) pockets. Various novel approaches have been used to design preorganized, depeptidized macrocyclic inhibitors linking the P(2)-P(4) groups and P(1)-P(3) residues. OBJECTIVE: The article summarizes efforts by various groups to develop inhibitors that bind to the active site and inhibit viral replication. METHOD: Review of recent patents and scientific literature. CONCLUSION: Macrocyclization has proved to be an effective tool for depeptidization of peptidic inhibitors with improved binding and pharmacokinetic properties.
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