Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 49, Pages 20986-20991Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1006370107
Keywords
drug design; hepatitis C; substrate envelope
Categories
Funding
- National Institute of Health (NIH) [R01-GM65347, R01-AI085051]
- Department of Energy (DOE), Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]
- NIH-NCRR [RR007707]
- Michigan Economic Development Corporation
- Michigan Technology TriCorridor [085P1000817]
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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.
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