Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding
- 17 November 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (49), 20986-20991
- https://doi.org/10.1073/pnas.1006370107
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.Keywords
This publication has 62 references indexed in Scilit:
- Identification of HCV protease inhibitor resistance mutations by selection pressure-based methodNucleic Acids Research, 2009
- Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patientsHepatology, 2008
- HIV-1 Protease Inhibitors from Inverse Design in the Substrate Envelope Exhibit Subnanomolar Binding to Drug-Resistant VariantsJournal of the American Chemical Society, 2008
- Computational design and experimental study of tighter binding peptides to an inactivated mutant of HIV‐1 proteaseProteins-Structure Function and Bioinformatics, 2008
- Inference of Macromolecular Assemblies from Crystalline StateJournal of Molecular Biology, 2007
- Phasercrystallographic softwareJournal of Applied Crystallography, 2007
- MolProbity: all-atom contacts and structure validation for proteins and nucleic acidsNucleic Acids Research, 2007
- The Protein Data BankNucleic Acids Research, 2000
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997
- Free R value: a novel statistical quantity for assessing the accuracy of crystal structuresNature, 1992