UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

2010-12-07

Document Type

Article

Subjects

Carrier Proteins; Catalytic Domain; Crystallography, X-Ray; *Drug Design; *Drug Resistance, Viral; Hepacivirus; Humans; Mutation; Protease Inhibitors; Protein Binding; Substrate Specificity; Viral Nonstructural Proteins; inhibitors; Viral Proteins

Disciplines

Biochemistry, Biophysics, and Structural Biology | Microbiology

Abstract

Hepatitis C virus infects an estimated 180 million people worldwide, prompting enormous efforts to develop inhibitors targeting the essential NS3/4A protease. Resistance against the most promising protease inhibitors, telaprevir, boceprevir, and ITMN-191, has emerged in clinical trials. In this study, crystal structures of the NS3/4A protease domain reveal that viral substrates bind to the protease active site in a conserved manner defining a consensus volume, or substrate envelope. Mutations that confer the most severe resistance in the clinic occur where the inhibitors protrude from the substrate envelope, as these changes selectively weaken inhibitor binding without compromising the binding of substrates. These findings suggest a general model for predicting the susceptibility of protease inhibitors to resistance: drugs designed to fit within the substrate envelope will be less susceptible to resistance, as mutations affecting inhibitor binding would simultaneously interfere with the recognition of viral substrates.

DOI of Published Version

10.1073/pnas.1006370107

Source

Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20986-91. Epub 2010 Nov 17. Link to article on publisher's site

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

21084633

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