Discovery of the First Thumb Pocket 1 NS5B Polymerase Inhibitor (BILB 1941) with Demonstrated Antiviral Activity in Patients Chronically Infected with Genotype 1 Hepatitis C Virus (HCV)

2012 ◽  
Vol 55 (17) ◽  
pp. 7650-7666 ◽  
Author(s):  
Pierre L. Beaulieu ◽  
Michael Bös ◽  
Michael G. Cordingley ◽  
Catherine Chabot ◽  
Gulrez Fazal ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Genotype 1 ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Ns5b Polymerase

scholarly journals In VitroAntiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

2016 ◽  
Vol 60 (3) ◽  
pp. 1847-1853 ◽  
Author(s):  
Guofeng Cheng ◽  
Yang Tian ◽  
Brian Doehle ◽  
Betty Peng ◽  
Amoreena Corsa ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Fixed Dose ◽  
Resistance Profile ◽  
Direct Acting Antiviral ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Ns5b Polymerase

Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, includingin vitropotency,in vitroresistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC50) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC50values of 0.11 to 1.1 nM. LDV has relatively lessin vitroantiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC50values of 16 to 530 nM.In vitroresistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment.In vitroantiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC50values equivalent to those for the wild type.

Formal Synthesis of Hepatitis C Virus NS5B Polymerase Inhibitor

Synlett ◽  
2013 ◽  
Vol 24 (16) ◽  
pp. 2143-2147 ◽  
Author(s):  
Hidetoshi Tokuyama ◽  
Takahiro Noro ◽  
Kentaro Okano
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Formal Synthesis ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Ns5b Polymerase

scholarly journals Potency and Resistance Analysis of Hepatitis C Virus NS5B Polymerase Inhibitor BMS-791325 on All Major Genotypes

2014 ◽  
Vol 58 (12) ◽  
pp. 7416-7423 ◽  
Author(s):  
Mengping Liu ◽  
Maria Tuttle ◽  
Min Gao ◽  
Julie A. Lemm
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Chronic Infections ◽  
Thumb Domain ◽  
Ns5b Polymerase Inhibitor ◽  
Chimeric Replicon ◽  
Polymerase Inhibitor ◽  
Ns3 Protease ◽  
Hybrid Clones ◽  
Ns5b Polymerase

ABSTRACTBMS-791325 is a hepatitis C virus (HCV) inhibitor binding to the thumb domain of the NS5B RNA-dependent RNA polymerase. BMS-791325 is well characterized in genotype 1 (GT1) and exhibits good inhibitory activity (50% effective concentration [EC50], <10 nM) against hybrid replicons containing patient NS5B sequences from GT3a, -4a, and -5a while potency against GT2 is significantly reduced (J. A. Lemm et al., Antimicrob. Agents Chemother. 58:3485–3495, 2014, doi:http://dx.doi.org/10.1128/AAC.02495-13). BMS-791325 potency against GT6a hybrid replicons is more variable, with two of three hybrid clones having EC50s similar to that for GT1 while a third patient clone was ∼10 times less susceptible to BMS-791325. To characterize the resistance profile of BMS-791325 beyond GT1, curing studies were performed across GT1a and -3a to -6a and demonstrated that GT1a has the highest resistance barrier versus BMS-791325 while GT6a has the lowest. Selection of GT3 to -6 NS5B chimeric replicon cells at different concentrations of BMS-791325 revealed substitutions in the thumb domain of NS5B at residues 494 and 495 that conferred different levels of resistance to BMS-791325 but remained susceptible to NS5A or NS3 protease inhibitors. In addition, we demonstrate that the reduced potency of BMS-791325 against one GT6a patient is due to an A494 polymorphism present in ∼21% of sequences in the European HCV database. The results from this report suggest that BMS-791325 is a candidate for combination treatment of HCV GT3 to -6 chronic infections, and the resistance profiles identified will provide useful information for future clinical development.

scholarly journals Discovery of SCH 900188: A Potent Hepatitis C Virus NS5B Polymerase Inhibitor Prodrug As a Development Candidate

2013 ◽  
Vol 5 (3) ◽  
pp. 244-248 ◽  
Author(s):  
Kevin X. Chen ◽  
Srikanth Venkatraman ◽  
Gopinadhan N. Anilkumar ◽  
Qingbei Zeng ◽  
Charles A. Lesburg ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Ns5b Polymerase
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