Reversion of naturally occurring high-level resistance mutations to NS3 protease inhibitors in two treatment-naive individuals infected with hepatitis C virus

2013 ◽  
Vol 68 (6) ◽  
pp. 1448-1450 ◽  
Author(s):  
S. Bagaglio ◽  
E. Messina ◽  
C. Uberti-Foppa ◽  
M. Merli ◽  
L. D. Torre ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Resistance Mutations ◽  
Naturally Occurring ◽  
Ns3 Protease Inhibitors ◽  
Treatment Naïve ◽  
High Level ◽  
Ns3 Protease ◽  
Level Resistance

scholarly journals Analysis of Naturally Occurring Resistant Mutations to Hepatitis C Virus NS3 Protease Inhibitors: A Preliminary Study in South of Iran

2015 ◽  
Vol 8 (10) ◽  
Author(s):  
Mozhgan Afrasiabi ◽  
Seyed Younes Hosseini ◽  
Ramin Yaghobi ◽  
Mohammad-Reza Fattahi ◽  
Maryam Ardebili ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Naturally Occurring ◽  
Ns3 Protease Inhibitors ◽  
Preliminary Study ◽  
Ns3 Protease

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

Development of hepatitis C virus chimeric replicons for identifying broad spectrum NS3 protease inhibitors

2011 ◽  
Vol 91 (2) ◽  
pp. 102-111 ◽  
Author(s):  
Joseph Binder ◽  
Selwyna Tetangco ◽  
Megan Weinshank ◽  
Karen Maegley ◽  
Laura Lingardo ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Broad Spectrum ◽  
Ns3 Protease Inhibitors ◽  
Ns3 Protease

scholarly journals Selection of Replicon Variants Resistant to ACH-806, a Novel Hepatitis C Virus Inhibitor with No Cross-Resistance to NS3 Protease and NS5B Polymerase Inhibitors

2008 ◽  
Vol 52 (6) ◽  
pp. 2043-2052 ◽  
Author(s):  
Wengang Yang ◽  
Yongsen Zhao ◽  
Joanne Fabrycki ◽  
Xiaohong Hou ◽  
Xingtie Nie ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Protease Inhibitors ◽  
Cross Resistance ◽  
Polymerase Inhibitors ◽  
Ns3 Protease Inhibitors ◽  
Ns3 Protease ◽  
Ns5b Polymerase ◽  
Selection Of

ABSTRACT We have discovered a novel class of compounds active against hepatitis C virus (HCV), using a surrogate cellular system, HCV replicon cells. The leading compound in the series, ACH-806 (GS-9132), is a potent and specific inhibitor of HCV. The selection of resistance replicon variants against ACH-806 was performed to map the mutations conferring resistance to ACH-806 and to determine cross-resistance profiles with other classes of HCV inhibitors. Several clones emerged after the addition of ACH-806 to HCV replicon cells at frequencies and durations similar to that observed with NS3 protease inhibitors and NS5B polymerase inhibitors. Phenotypic analyses of these clones revealed that they are resistant to ACH-806 but remain sensitive to other classes of HCV inhibitors. Moreover, no significant change in the susceptibility to ACH-806 was found when the replicon cellular clones resistant to NS3 protease inhibitors and NS5B polymerase inhibitors were examined. Sequencing of the entire coding region of ACH-806-resistant replicon variants yielded several consensus mutations. Reverse genetics identified two single mutations in NS3, a cysteine-to-serine mutation at amino acid 16 and an alanine-to-valine mutation at amino acid 39, that are responsible for the resistance of the replicon variants to ACH-806. Both mutations are located at the N terminus of NS3 where extensive interactions with the central hydrophobic region of NS4A exist. These data provide evidence that ACH-806 inhibits HCV replication by a novel mechanism.

scholarly journals In VitroActivity of Simeprevir against Hepatitis C Virus Genotype 1 Clinical Isolates and Its Correlation with NS3 Sequence and Site-Directed Mutants

2015 ◽  
Vol 59 (12) ◽  
pp. 7548-7557 ◽  
Author(s):  
Thierry Verbinnen ◽  
Bart Fevery ◽  
Leen Vijgen ◽  
Tom Jacobs ◽  
Sandra De Meyer ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Genotype 1 ◽  
Low Level ◽  
Fold Reduction ◽  
Hcv Genotype 1 ◽  
High Level ◽  
Ns3 Protease ◽  
Level Resistance

ABSTRACTSimeprevir (TMC435) is a once-daily, single-pill, oral hepatitis C virus (HCV) NS3 protease inhibitor approved for the treatment of chronic HCV infection. Phenotypic characterization of baseline isolates and isolates from HCV genotype 1-infected patients failing with a simeprevir-based regimen was performed using chimeric replicons carrying patient-derived NS3 protease sequences. Cutoff values differentiating between full susceptibility to simeprevir (≤2.0-fold reduction in simeprevir activity) and low-level versus high-level resistance (≥50-fold reduction in simeprevir activity) were determined. The median simeprevir fold change in the 50% effective concentration (FC) of pretreatment genotype 1a isolates, with and without Q80K, and genotype 1b isolates was 11, 0.9, and 0.4, respectively. Naturally occurring NS3 polymorphisms that reduced simeprevir activity, other than Q80K, were uncommon in the simeprevir studies and generally conferred low-level resistancein vitro. Although the proportion of patients with failure differed by HCV geno/subtype and/or presence of baseline Q80K, the level of simeprevir resistance observed at failure was similarly high irrespective of type of failure, HCV genotype 1 subtype, and presence or absence of baseline Q80K. At the end of the study, simeprevir activity against isolates that lost the emerging amino acid substitution returned to pretreatment values. Activity of simeprevir against clinical isolates and site-directed mutant replicons harboring the corresponding single or double amino acid substitutions correlated well, showing that simeprevir resistance can be attributed to these substitutions. In conclusion, pretreatment NS3 isolates were generally fully susceptible (FC, ≤2.0) or conferred low-level resistance to simeprevirin vitro(FC, >2.0 and <50). Treatment failure with a simeprevir-based regimen was associated with emergence of high-level-resistance variants (FC, ≥50).

scholarly journals Specific Detection of Naturally Occurring Hepatitis C Virus Mutants with Resistance to Telaprevir and Boceprevir (Protease Inhibitors) among Treatment-Naive Infected Individuals

2011 ◽  
Vol 50 (2) ◽  
pp. 281-287 ◽  
Author(s):  
S. Fonseca-Coronado ◽  
A. Escobar-Gutierrez ◽  
K. Ruiz-Tovar ◽  
M. Y. Cruz-Rivera ◽  
P. Rivera-Osorio ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Specific Detection ◽  
Naturally Occurring ◽  
Treatment Naïve
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