Conformational Changes in Human Hepatitis C Virus NS3 Protease upon Binding of Product-Based Inhibitors†

Biochemistry ◽  
1999 ◽  
Vol 38 (42) ◽  
pp. 13844-13852 ◽  
Author(s):  
Elisabetta Bianchi ◽  
Stefania Orrù ◽  
Fabrizio Dal Piaz ◽  
Raffaele Ingenito ◽  
Annarita Casbarra ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Conformational Changes ◽  
Human Hepatitis ◽  
Ns3 Protease

Potent Peptide Inhibitors of Human Hepatitis C Virus NS3 Protease Are Obtained by Optimizing the Cleavage Products

Biochemistry ◽  
1998 ◽  
Vol 37 (25) ◽  
pp. 8906-8914 ◽  
Author(s):  
Paolo Ingallinella ◽  
Sergio Altamura ◽  
Elisabetta Bianchi ◽  
Marina Taliani ◽  
Raffaele Ingenito ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Peptide Inhibitors ◽  
Human Hepatitis ◽  
Ns3 Protease

scholarly journals Conformational changes in the NS3 protease from hepatitis C virus strain Bk monitored by limited proteolysis and mass spectrometry

1999 ◽  
Vol 8 (7) ◽  
pp. 1445-1454 ◽  
Author(s):  
Stefania Orrù ◽  
Fabrizio Dal Piaz ◽  
Annarita Casbarra ◽  
Gabriella Biasiol ◽  
Raffaele De Francesco ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Strain ◽  
Conformational Changes ◽  
Limited Proteolysis ◽  
Ns3 Protease

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.

Phenylglycine as a novel P2 scaffold in hepatitis C virus NS3 protease inhibitors

2007 ◽  
Vol 15 (3) ◽  
pp. 1448-1474 ◽  
Author(s):  
Pernilla Örtqvist ◽  
Shane D. Peterson ◽  
Eva Åkerblom ◽  
Thomas Gossas ◽  
Yogesh A. Sabnis ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Ns3 Protease Inhibitors ◽  
Ns3 Protease
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