Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance

Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach toward the identification of a macrocyclic acylsulfonamide that is a potent inhibitor o...

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Bibliographic Details
Published in:The Journal of biological chemistry 2013-02, Vol.288 (8), p.5673-5681
Main Authors: O'Meara, Jeff A., Lemke, Christopher T., Godbout, Cédrickx, Kukolj, George, Lagacé, Lisette, Moreau, Benoît, Thibeault, Diane, White, Peter W., Llinàs-Brunet, Montse
Format: Article
Language:English
Subjects:
Antiviral Agents
Antiviral Agents - pharmacology
Antiviral Resistance
Carrier Proteins - chemistry
Cell Line
Cloning, Molecular
Crystallography, X-Ray - methods
Drug Resistance
Drug Resistance, Viral
Genotype
HCV NS3/4A Inhibitor
HCV NS3/4A Protease
Hepatitis C - drug therapy
Hepatitis C Virus
Humans
Intracellular Signaling Peptides and Proteins
Models, Chemical
Models, Molecular
Molecular Bases of Disease
Molecular Conformation
Protease Inhibitors - pharmacology
Serine Protease
Sulfonamides - chemistry
Viral Nonstructural Proteins - chemistry
X-ray Crystallography
X-Rays
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Summary:Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach toward the identification of a macrocyclic acylsulfonamide that is a potent inhibitor of the NS3-NS4A proteases of all hepatitis C virus genotypes and of a panel of genotype 1-resistant variants. The enhanced potency of this compound versus variants D168V and R155K facilitated x-ray determination of the inhibitor-variant complexes. In turn, these structural studies revealed a complex molecular basis of resistance and rationalized how such compounds are able to circumvent these mechanisms. Background: Antivirals must often be given in combinations to avoid rapid emergence of resistance. Results: We identified and structurally characterized protease inhibitors that maintain potency against genotype and resistant variants. Conclusion: Pan-variant potency was achieved by targeting invariant regions and incorporating flexibility where pocket variability occurs. Significance: Such inhibitors may yield simplified and/or more successful treatments for hepatitis C infections.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.439455