<i>In Vitro</i>
            Activity of BMS-790052 on Hepatitis C Virus Genotype 4 NS5A

Wang, Chunfu; Jia, Lingling; Huang, Han-Yao; Qiu, Dike; Valera, Lourdes; Huang, Xin; Sun, Jin-Hua; Nower, Peter T.; O’Boyle, Donald R.; Gao, Min; Fridell, Robert A.

doi:10.1128/aac.06169-11

Cited by 42 publications

(32 citation statements)

References 10 publications

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“…Resistance-associated amino acid substitutions in NS5A were observed at positions similar to those reported for other genotypes within the first 100 amino acids (aa) of NS5A. The availability of GT-5a and GT-6a NS5A hybrid replicons, together with authentic or hybrid replicons from genotypes 1 to 4 (2,(14)(15)(16), enabled direct comparison of the resistance barriers of DCV in these diverse genotypes by using replicon elimination assays (13). These studies revealed that GT-1b has the highest barrier of resistance to DCV, while GT-2a has the lowest resistance barrier, with a relative rank order of 1b Ͼ 4a Ն 5a Ͼ 6a Х 1a Ͼ 2a JFH Ͼ 3a Ͼ 2a M31.…”

Section: Aclatasvir (Dcv [Bms-790052]) Is a Cross-genotypic Ns5amentioning

confidence: 68%

“…Prior studies using the in vitro replicon system indicated that DCV should be an effective antiviral agent against HCV genotypes 1 to 4 (2,(13)(14)(15)(16). Here, we report the antiviral activity and resistance profiles of DCV against hybrid replicons with NS5A sequences derived from GT-5a and GT-6a clinical isolates.…”

Section: Aclatasvir (Dcv [Bms-790052]) Is a Cross-genotypic Ns5amentioning

confidence: 99%

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Comparison of Daclatasvir Resistance Barriers on NS5A from Hepatitis C Virus Genotypes 1 to 6: Implications for Cross-Genotype Activity

Wang

Jia

O’Boyle

et al. 2014

Antimicrob Agents Chemother

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A comparison of the daclatasvir (DCV [BMS-790052]) resistance barrier on authentic or hybrid replicons containing NS5A from hepatitis C virus (HCV) genotypes 1 to 6 (GT-1 to -6) was completed using a replicon elimination assay. The data indicated that genotype 1b (GT-1b) has the highest relative resistance barrier and genotype 2a (GT-2a M31) has the lowest. The rank order of resistance barriers to DCV was 1b > 4a > 5a > 6a Х 1a > 2a JFH > 3a > 2a M31. Importantly, DCV in combination with a protease inhibitor (PI) eliminated GT-2a M31 replicon RNA at a clinically relevant concentration. Previously, we reported the antiviral activity and resistance profiles of DCV on HCV genotypes 1 to 4 evaluated in the replicon system. Here, we report the antiviral activity and resistance profiles of DCV against hybrid replicons with NS5A sequences derived from HCV GT-5a and GT-6a clinical isolates. DCV was effective against both GT-5a and -6a hybrid replicon cell lines (50% effective concentrations [EC 50 s] ranging from 3 to 7 pM for GT-5a, and 74 pM for GT-6a). Resistance selection identified amino acid substitutions in the N-terminal domain of NS5A. For GT-5a, L31F and L31V, alone or in combination with K56R, were the major resistance variants (EC 50 s ranging from 2 to 40 nM). In GT-6a, Q24H, L31M, P32L/S, and T58A/S were identified as resistance variants (EC 50 s ranging from 2 to 250 nM). The in vitro data suggest that DCV has the potential to be an effective agent for HCV genotypes 1 to 6 when used in combination therapy. D aclatasvir (DCV [BMS-790052]) is a cross-genotypic NS5Ainhibitor with picomolar to low nanomolar potency in the replicon system (1, 2). The antiviral activity of DCV in vitro translated into clinical efficacy, with hepatitis C virus (HCV) RNA declines of ϳ3 to 4 log 10 observed in genotype 1a (GT-1a)-infected subjects treated once daily (QD) with 60 mg of DCV in a 14-day multiple ascending dose (MAD) monotherapy study (3, 4). Moreover, DCV was effective against GT-1b and -1a in combinations that include either pegylated interferon and ribavirin (PEG-IFN-RBV) or other direct-acting anti-HCV agents (DAAs) (5-8).There are large populations of viral quasispecies preexisting in infected individuals, and variants that confer resistance to antiviral agents can be rapidly enriched and/or selected during antiviral treatment (9-11). Since DCV resistance variants show no crossresistance to other DAAs, DCV should rapidly suppress wild-type virus and variants resistant to other DAAs, thereby enhancing the effectiveness of other DAAs in combination therapies (2, 3). This effect is predicted to lead to higher rates of sustained viral response (SVR) and/or shorten the duration of treatment necessary to achieve SVR. Recent clinical results with DCV plus asunaprevir (ASV ) in patients infected with GT-1b and with DCV plus sofosbuvir (SOF ) in patients infected with GT-1, -2, and 3 demonstrate the effectiveness of DCV in interferon-free DAA combination therapies (6,12).Prior studies using the in vitro replicon system in...

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Section: Aclatasvir (Dcv [Bms-790052]) Is a Cross-genotypic Ns5amentioning

confidence: 68%

Section: Aclatasvir (Dcv [Bms-790052]) Is a Cross-genotypic Ns5amentioning

confidence: 99%

Comparison of Daclatasvir Resistance Barriers on NS5A from Hepatitis C Virus Genotypes 1 to 6: Implications for Cross-Genotype Activity

Wang

Jia

O’Boyle

et al. 2014

Antimicrob Agents Chemother

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“…BMS-791325 was synthesized at Bristol-Myers Squibb. Daclatasvir (DCV; NS5A replication complex inhibitor) and asunaprevir (ASV; NS3 protease inhibitor) were previously described (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39).…”

Section: Cell Lines and Hcv Inhibitorsmentioning

confidence: 99%

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

Liu

Tuttle

Gao

et al. 2014

Antimicrob Agents Chemother

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BMS-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 [EC 50 ], <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 EC 50 s similar to that for GT1 while a third patient clone was ϳ10 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 ϳ21% 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.

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“…However, the increased incidence of adverse events associated with interferon-based regimens triggered the development of interferon-free therapeutic combinations . In vitro studies show that daclatasvir, an NS5A inhibitor, has a pan-genotypic activity with picomolar potency and pharmacokinetic characteristics allowing for single daily dosage regimens Wang et al, 2012). It acts via inhibiting the NS3 protease enzyme and therefore, preventing NS5A hyperphosphorylation, leading to inhibition of viral replication complex formation (Lee et al, 2011;Qiu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Hezode et al (2014) reported that patients with CC IL28B genotype had a higher chance of achieving SVR, compared to those with a non-CC genotype, regardless of therapy . Also, as shown by in vivo and in vitro studies, the combination of L30 polymorphism and IL28B non-CC genotype can significantly increase daclatasvir resistance (Wang et al, 2012;Wang et al, 2014).…”

mentioning

confidence: 99%

Efficacy of daclatasvir plus peginterferon alfa and ribavirin for patients with chronic hepatitis C genotype 4 infection

Ahmed

Abushouk

Gadelkarim

et al. 2017

Bangladesh J Pharmacol

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Clinical trials evaluating the safety and efficacy of daclatasvir for chronic hepatitis C virus (HCV) genotype 4 infection are scarce and yet with small sample sizes. Therefore, we conducted this systematic review to investigate the efficacy of daclatasvir in HCV genotype 4 treatment. A computer literature search of PubMed, Scopus, Embase, Ovid, Web of knowledge, and Cochrane central was conducted. We selected studies comparing daclatasvir plus peginterferon-alfa/ribavirin versus placebo plus peginterferon-alfa/ ribavirin in patients with HCV genotype 4 infection. Pooling data from two randomized controlled trials (n = 154 patients) showed that daclatasvir/peginterferon/ribavirin treatment achieved a moderate sustained virologic response rate of 76% after 12 weeks and of 79% after 24 weeks. The daclatasvir containing regimen was superior to the placebo containing regimen in terms of virologic response rates after 12 weeks (RR=1.9% CI 1.3 to 2.6) and 24 weeks (RR=1.8% CI 1.3 to 2.5). More effective regimens are needed for HCV genotype 4. Article InfoReceived:10 October 2016 Accepted:13

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In Vitro Activity of BMS-790052 on Hepatitis C Virus Genotype 4 NS5A

Cited by 42 publications

References 10 publications

Comparison of Daclatasvir Resistance Barriers on NS5A from Hepatitis C Virus Genotypes 1 to 6: Implications for Cross-Genotype Activity

Comparison of Daclatasvir Resistance Barriers on NS5A from Hepatitis C Virus Genotypes 1 to 6: Implications for Cross-Genotype Activity

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

Efficacy of daclatasvir plus peginterferon alfa and ribavirin for patients with chronic hepatitis C genotype 4 infection

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