Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A.

Abstract

It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by ~3-4 log10 in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.

• Authors: Jin-Hua Sun, Donald R O'Boyle 2nd, Robert A Fridell, David R Langley, Chunfu Wang, Susan B Roberts, Peter Nower, Benjamin M Johnson, Frederic Moulin, Michelle J Nophsker, Ying-Kai Wang, Mengping Liu, Karen Rigat, Yong Tu, Piyasena Hewawasam, John Kadow, Nicholas A Meanwell, Mark Cockett, Julie A Lemm, Melissa Kramer, Makonen Belema, Min Gao
• Journal: Nature (Nature) Vol. 527 Issue 7577 Pg. 245-8 (Nov 12 2015) ISSN: 1476-4687 [Electronic] England
• PMID: 26536115 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Biphenyl Compounds
• Carbamates
• Imidazoles
• Pyrrolidines
• Syn-395
• Viral Nonstructural Proteins
• NS-5 protein, hepatitis C virus
• Valine
• daclatasvir

Topics

• Allosteric Regulation (drug effects)
• Animals
• Antiviral Agents (pharmacology)
• Biphenyl Compounds (pharmacology)
• Carbamates
• Cell Line
• Drug Resistance, Viral (drug effects)
• Drug Synergism
• Drug Therapy, Combination
• Hepacivirus (drug effects, genetics, metabolism)
• Hepatitis C (virology)
• Hepatocytes (transplantation)
• Humans
• Imidazoles (pharmacology)
• Mice
• Models, Molecular
• Protein Conformation (drug effects)
• Protein Multimerization (drug effects)
• Protein Structure, Quaternary (drug effects)
• Pyrrolidines
• Reproducibility of Results
• Valine (analogs & derivatives)
• Viral Nonstructural Proteins (chemistry, genetics, metabolism)
• Virus Replication (drug effects)