<i>In Vitro</i>
            Activity of Daclatasvir on Hepatitis C Virus Genotype 3 NS5A

Wang, Chunfu; Valera, Lourdes; Jia, Lingling; Kirk, Melissa; Gao, Min; Fridell, Robert A.

doi:10.1128/aac.01874-12

Cited by 46 publications

(43 citation statements)

References 21 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 Ns5asupporting

confidence: 62%

“…L31F or L31V variants have also been found to be associated with resistance to DCV in GT-1b, -1a, or -3a replicons (2,13,15). Prior studies also identified amino acid substitutions at NS5A residues 54, 58, or 62 in association with DCV resistance in genotype 1 replicons (2,3,13,25), but the K56R change observed here is the first indication that substitutions at residue 56 can contribute to resistance.…”

Section: Discussionsupporting

confidence: 51%

“…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: 88%

“…A GT-2a M31 replicon was similarly constructed with sequences encoding amino acids 1 to 425 amplified by PCR from a pJ6CF infectious clone (20). The resulting replicons encoded NS5A proteins with amino acids 1 to 430, 1 to 431, and 1 to 425 derived from GT-5a, GT-6a, and GT-2a J6CF, respectively, and an additional 41 C-terminal amino acids from the parental JFH1 strain (15). Replicon sequences were confirmed by sequencing analysis.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

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 Ns5asupporting

confidence: 62%

Section: Discussionsupporting

confidence: 51%

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

confidence: 88%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

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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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Genetic and Biochemical Characterization of VMB‐1, a Novel Metallo‐β‐Lactamase Encoded by a Conjugative, Broad‐Host Range IncC Plasmid from Vibrio spp

et al. 2020

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The increasing incidence of phenotypic resistance to carbapenems in recent years is mainly attributed to acquisition of mobile carbapenemase‐encoding genetic elements by major bacterial pathogens. Here, a novel carbapenemase known as Vibrio metallo‐β‐lactamase 1 (VMB‐1), which is encoded by a gene (blaVMB‐1) located in an integron‐bearing, highly transmissible IncC type plasmid, namely pVB1796, is identified and characterized, both genetically and functionally. Recovered from a foodborne Vibrio alginolyticus strain that exhibits resistance to all known β‐lactam antibiotics, pVB1796 is found to possess a hybrid backbone that exhibits unique features of both type 1 and type 2 IncC elements. VMB‐1 exhibits 94% sequence homology with several recently reported but poorly characterized metallo‐β‐lactamases (MBLs) produced by the marine organisms Alteromonadaceae, Glaciecola, and Thalassomonas actiniarum. Sequence alignment analysis shows that VMB‐1 shares a structurally identical active site with subclass B1 MBLs. Importantly, pVB1796 is found to be efficiently transferred from Vibrio to other Gram‐negative bacterial pathogens, including Salmonella typhimurium, Klebsiella pneumoniae, and Acinetobacter baumanni, via conjugation. These findings suggest that blaVMB‐1‐bearing plasmids have the potential to be disseminated to other Gram‐negative bacterial pathogens in the near future and render carbapenems useless in treatment of multidrug resistant infections.

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In Vitro Activity of Daclatasvir on Hepatitis C Virus Genotype 3 NS5A

Cited by 46 publications

References 21 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

Genetic and Biochemical Characterization of VMB‐1, a Novel Metallo‐β‐Lactamase Encoded by a Conjugative, Broad‐Host Range IncC Plasmid from Vibrio spp

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