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 Structural characterization of the Hepatitis C Virus NS3 protease from genotype 3a: The basis of the genotype 1b vs. 3a inhibitor potency shift

Virology ◽  
2010 ◽  
Vol 405 (2) ◽  
pp. 424-438 ◽  
Author(s):  
Mariana Gallo ◽  
Matthew James Bottomley ◽  
Matteo Pennestri ◽  
Tommaso Eliseo ◽  
Maurizio Paci ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Structural Characterization ◽  
Genotype 1B ◽  
Ns3 Protease ◽  
Genotype 3A

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 Structural characterization of the transmembrane proximal region of the hepatitis C virus E1 glycoprotein

2010 ◽  
Vol 1798 (3) ◽  
pp. 344-353 ◽  
Author(s):  
Roberta Spadaccini ◽  
Gerardino D'Errico ◽  
Viviana D'Alessio ◽  
Eugenio Notomista ◽  
Alessia Bianchi ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Structural Characterization ◽  
Proximal Region

scholarly journals In VitroResistance Profile of the Hepatitis C Virus NS3 Protease Inhibitor BI 201335

2011 ◽  
Vol 56 (1) ◽  
pp. 569-572 ◽  
Author(s):  
Lisette Lagacé ◽  
Peter W. White ◽  
Christiane Bousquet ◽  
Nathalie Dansereau ◽  
Florence Dô ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Alpha Interferon ◽  
Phenotypic Characterization ◽  
Genotype 1A ◽  
Ns3 Protease

ABSTRACTThein vitroresistance profile of BI 201335 was evaluated through selection and characterization of variants in genotype 1a (GT 1a) and genotype 1b (GT 1b) replicons. NS3 R155K and D168V were the most frequently observed resistant variants. Phenotypic characterization of the mutants revealed shifts in sensitivity specific to BI 201335 that did not alter susceptibility to alpha interferon. In contrast to macrocyclic and covalent protease inhibitors, changes at V36, T54, F43, and Q80 did not confer resistance to BI 201335.

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.

Structural characterization of the 5′ untranslated RNA of hepatitis C virus by vibrational spectroscopy

2006 ◽  
Vol 124 (1) ◽  
pp. 73-79 ◽  
Author(s):  
Arantxa Rodríguez-Casado ◽  
Javier Bartolomé ◽  
Vicente Carreño ◽  
Marina Molina ◽  
Pedro Carmona
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Vibrational Spectroscopy ◽  
Structural Characterization

scholarly journals Preclinical Characterization of the Antiviral Activity of SCH 900518 (Narlaprevir), a Novel Mechanism-Based Inhibitor of Hepatitis C Virus NS3 Protease

2010 ◽  
Vol 54 (6) ◽  
pp. 2365-2370 ◽  
Author(s):  
X. Tong ◽  
A. Arasappan ◽  
F. Bennett ◽  
R. Chase ◽  
B. Feld ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Drug Exposure ◽  
Covalent Bond ◽  
Alpha Interferon ◽  
Cross Resistance ◽  
Reversible Covalent ◽  
Ns3 Protease

ABSTRACT Small-molecule hepatitis C virus (HCV) NS3 protease inhibitors such as boceprevir (SCH 503034) have been shown to have antiviral activity when they are used as monotherapy and in combination with pegylated alpha interferon and ribavirin in clinical trials. Improvements in inhibitor potency and pharmacokinetic properties offer opportunities to increase drug exposure and to further increase the sustained virological response. Exploration of the structure-activity relationships of ketoamide inhibitors related to boceprevir has led to the discovery of SCH 900518, a novel ketoamide protease inhibitor which forms a reversible covalent bond with the active-site serine. It has an overall inhibition constant (K*i) of 7 nM and a dissociation half-life of 1 to 2 h. SCH 900518 inhibited replicon RNA at a 90% effective concentration (EC90) of 40 nM. In biochemical assays, SCH 900518 was active against proteases of genotypes 1 to 3. A 2-week treatment with 5× EC90 of the inhibitor reduced the replicon RNA level by 3 log units. Selection of replicon cells with SCH 900518 resulted in the outgrowth of several resistant mutants (with the T54A/S and A156S/T/V mutations). Cross-resistance studies demonstrated that the majority of mutations for resistance to boceprevir and telaprevir caused similar fold losses of activity against all three inhibitors; however, SCH 900518 retained more activity against these mutants due to its higher intrinsic potency. Combination treatment with alpha interferon enhanced the inhibition of replicon RNA and suppressed the emergence of resistant replicon colonies, supporting the use of SCH 900518-pegylated alpha interferon combination therapy in the clinic. In summary, the results of the preclinical characterization of the antiviral activity of SCH 900518 support its evaluation in clinical studies.

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
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