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 Peptide Inhibitors of Hepatitis C Virus NS3 Protease

2003 ◽  
Vol 14 (5) ◽  
pp. 225-233 ◽  
Author(s):  
Sergio Portal-Núñez ◽  
Carlos J González-Navarro ◽  
Marina García-Delgado ◽  
José Luis Vizmanos ◽  
Juan José Lasarte ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Amino Acid Replacement ◽  
Peptide Inhibitors ◽  
Large Numbers ◽  
Prevalent Virus ◽  
Ns3 Protease ◽  
Leading Compounds

Hepatitis C virus (HCV) is a highly prevalent virus and one of the major agents of chronic hepatitis. Since HCV NS3 protease is essential for the processing of HCV polyprotein, this protease is a target of choice to control HCV replication. Peptide inhibitors of NS3 were developed by selective amino acid replacement of six leader sequences, corresponding to regions of HCV polyprotein that are cleaved by NS3. The large numbers of potential 14-mer and 16-mer peptide inhibitors thus obtained were tested against NS3 using the fluorescent probe RETS1 and peptide cofactor SVVIVGRIILSGRA from NS4A protein. This afforded several peptide inhibitors with an IC50 of around 2 μM. These peptides may be good leading compounds for the development of peptidomimetics to control HCV replication in the treatment of chronic hepatitis C.

Molecular docking of peptide inhibitors to the hepatitis C virus NS3 protease

2006 ◽  
pp. 472-473
Author(s):  
Mark Shenderovich ◽  
Jing Wang ◽  
Cindy Fisher ◽  
Kalyanaraman Ramnarayan ◽  
Ruben Abagyan
Keyword(s):  
Molecular Docking ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Peptide Inhibitors ◽  
Ns3 Protease

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

NMR Structural Characterization of Peptide Inhibitors Bound to the Hepatitis C Virus NS3 Protease:  Design of a New P2 Substituent

2004 ◽  
Vol 47 (1) ◽  
pp. 123-132 ◽  
Author(s):  
Nathalie Goudreau ◽  
Dale R. Cameron ◽  
Pierre Bonneau ◽  
Vida Gorys ◽  
Céline Plouffe ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Structural Characterization ◽  
Peptide Inhibitors ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document