Resistance of hepatitis C virus to NS3-4A protease inhibitors : mechanisms of drug resistance induced by R155Q, A156T, D168A and D168V mutations

One of the main issues in the development of antiviral therapy is the emergence of drug-resistant viruses. In the case of hepatitis C virus (HCV), selection of drug-resistant mutants was evidenced by in vitro studies on protease inhibitors (PIs); for example, BILN-2061, VX-950 and SCH-6. Four mutati...

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Published in:	Antiviral therapy Vol. 11; no. 7; pp. 847 - 855
Main Authors:	COURCOMBECK, Jérome, BOUZIDI, Mourad, PERBOST, Regis, JOUIROU, Besma, AMRONI, Nolwenn, CACOUB, Patrice, PEPE, Gérord, SABATIER, Jean-Marc, HOLFON, Philippe
Format:	Journal Article
Language:	English
Published:	London International Medical Press 01-01-2006
Subjects:	Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Binding Sites - genetics Biological and medical sciences Carbamates - chemistry Carbamates - pharmacology Drug Resistance, Viral Hepacivirus - drug effects Hepacivirus - enzymology Human viral diseases Infectious diseases Macrocyclic Compounds - chemistry Macrocyclic Compounds - pharmacology Medical sciences Models, Molecular Pharmacology. Drug treatments Point Mutation Quinolines - chemistry Quinolines - pharmacology Serine Endopeptidases - chemistry Serine Endopeptidases - drug effects Serine Endopeptidases - genetics Thiazoles - chemistry Thiazoles - pharmacology Viral diseases Viral hepatitis Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - chemistry Viral Nonstructural Proteins - drug effects Viral Nonstructural Proteins - genetics Treatment resistance Hepatic disease Induced resistance Infection Virus Viral disease Digestive diseases Antiviral Mutation Flaviviridae Mechanism of action Hepatitis C virus Hepacivirus Protease inhibitor Viral hepatitis C
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Summary:	One of the main issues in the development of antiviral therapy is the emergence of drug-resistant viruses. In the case of hepatitis C virus (HCV), selection of drug-resistant mutants was evidenced by in vitro studies on protease inhibitors (PIs); for example, BILN-2061, VX-950 and SCH-6. Four mutations in the HCV protease (R155Q, A156T, D168A and D168V) have been identified in vitro in the HCV replicon system that confer resistance to BILN-2061 (a reference inhibitor). However, the molecular mechanism of drug resistance is still unknown. The aim of this study is to unravel, using an molecular modelling strategy, the structural basis of such molecular mechanism of HCV resistance to PIs. We focused on protease mutations conferring HCV resistance to BILN-2061 and described for the first time such mechanism at a molecular level. The structures of drug-resistant NS3 proteases were obtained by mutation of selected residues (R155Q, A156T, D168A and D168V) and the ternary complexes formed between NS3-4A and BILN-2061 were optimized using GenMol software (www.3dgenoscience.com; Genoscience, Marseille, France). Two mechanisms were evidenced for viral resistance to BILN-2061. A 'direct' resistance mechanism is based on contacts between the mutated R155Q and A156T protease residues and its inhibitor. In the 'indirect' resistance mechanism, the mutated D168A/V residue is not in close contact with the drug itself but interacts with other residues connected to the drug. These data provide new insights in the understanding of the mechanisms of HCV drug escape, and may allow predicting potential cross-resistance phenomenon with other PIs. This approach can be used as a basis for future rational PI drug design candidates.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1359-6535 2040-2058
DOI:	10.1177/135965350601100702