Solution structure and dynamics of the single-chain hepatitis C virus NS3 protease NS4A cofactor complex

2001 ◽  
Vol 305 (5) ◽  
pp. 1099-1110 ◽  
Author(s):  
Mark A McCoy ◽  
Mary M Senior ◽  
Jennifer J Gesell ◽  
Lata Ramanathan ◽  
Daniel F Wyss
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Solution Structure ◽  
Single Chain ◽  
Structure And Dynamics ◽  
Ns3 Protease

scholarly journals Solution Structure of Substrate-based Ligands When Bound to Hepatitis C Virus NS3 Protease Domain

1999 ◽  
Vol 274 (26) ◽  
pp. 18618-18624 ◽  
Author(s):  
Steven R. LaPlante ◽  
Dale R. Cameron ◽  
Norman Aubry ◽  
Sylvain Lefebvre ◽  
George Kukolj ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Solution Structure ◽  
Protease Domain ◽  
Ns3 Protease

Non-Peptidic Small-Molecule Inhibitors of the Single-Chain Hepatitis C Virus NS3 Protease/NS4A Cofactor Complex Discovered by Structure-Based NMR Screening

2004 ◽  
Vol 47 (10) ◽  
pp. 2486-2498 ◽  
Author(s):  
Daniel F. Wyss ◽  
Ashok Arasappan ◽  
Mary M. Senior ◽  
Yu-Sen Wang ◽  
Brian M. Beyer ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Single Chain ◽  
Nmr Screening ◽  
Ns3 Protease

scholarly journals Engineering, characterization and phage display of hepatitis C virus NS3 protease and NS4A cofactor peptide as a single-chain protein

1998 ◽  
Vol 11 (12) ◽  
pp. 1257-1265 ◽  
Author(s):  
N. Dimasi ◽  
A. Pasquo ◽  
F. Martin ◽  
S. Di Marco ◽  
C. Steinkuhler ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Phage Display ◽  
Single Chain ◽  
Ns3 Protease

Binding Mode Determination of Benzimidazole Inhibitors of the Hepatitis C Virus RNA Polymerase by a Structure and Dynamics Strategy

2004 ◽  
Vol 116 (33) ◽  
pp. 4406-4411 ◽  
Author(s):  
Steven R. LaPlante ◽  
Araz Jakalian ◽  
Norman Aubry ◽  
Yves Bousquet ◽  
Jean-Marie Ferland ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Binding Mode ◽  
Hepatitis C Virus Rna ◽  
Structure And Dynamics ◽  
Virus Rna

scholarly journals Resistance Analysis of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir

2012 ◽  
Vol 56 (7) ◽  
pp. 3670-3681 ◽  
Author(s):  
Fiona McPhee ◽  
Jacques Friborg ◽  
Steven Levine ◽  
Chaoqun Chen ◽  
Paul Falk ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Clinical Studies ◽  
Replication Capacity ◽  
Replication Complex ◽  
Hcv Genotype ◽  
Genotype 1A ◽  
Genotype 1B ◽  
Ns3 Protease

ABSTRACTAsunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor demonstrating efficacy in alfa interferon-sparing, direct-acting antiviral dual-combination regimens (together with the NS5A replication complex inhibitor daclatasvir) in patients chronically infected with HCV genotype 1b. Here, we describe a comprehensivein vitrogenotypic and phenotypic analysis of asunaprevir-associated resistance against genotypes 1a and 1b using HCV replicons and patient samples obtained from clinical studies of short-term asunaprevir monotherapy. During genotype 1a resistance selection using HCV replicons, the primary NS3 protease substitutions identified were R155K, D168G, and I170T, which conferred low- to moderate-level asunaprevir resistance (5- to 21-fold) in transient-transfection susceptibility assays. For genotype 1b, a higher level of asunaprevir-associated resistance was observed at the same selection pressures, ranging from 170- to 400-fold relative to the wild-type control. The primary NS3 protease substitutions identified occurred predominantly at amino acid residue D168 (D168A/G/H/V/Y) and were associated with high-level asunaprevir resistance (16- to 280-fold) and impaired replication capacity. In asunaprevir single-ascending-dose and 3-day multiple-ascending-dose studies in HCV genotype 1a- or 1b-infected patients, the predominant pre-existing NS3 baseline polymorphism was NS3-Q80K. This substitution impacted initial virologic response rates in a single-ascending-dose study, but its effects after multiple doses were more ambiguous. Interestingly, for patient NS3 protease sequences containing Q80 and those containing K80, susceptibilities to asunaprevir were comparable when tested in an enzyme assay. No resistance-associated variants emerged in these clinical studies that significantly impacted susceptibility to asunaprevir. Importantly, asunaprevir-resistant replicons remained susceptible to an NS5A replication complex inhibitor, consistent with a role for asunaprevir in combination therapies.

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