Mechanism of Inhibition for BMS-791325, a Novel Non-nucleoside Inhibitor of Hepatitis C Virus NS5B Polymerase

Rigat, Karen; Lü, Hao; Wang, Ying-Kai; Argyrou, Argyrides; Fanslau, Caroline; Beno, Brett R.; Wang, Yi; Marcinkeviciene, Jovita; Ding, Min; Gentles, Robert G.; Gao, Min; Abell, Lynn M.; Roberts, Susan B.

doi:10.1074/jbc.m114.613653

Cited by 23 publications

(15 citation statements)

References 49 publications

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“…In vitro characterisation of beclabuvir revealed potent activity against HCV in recombinant enzyme assays and cell culture models, however, reduced potency was also observed against GT2, and variable activity against GT6 viruses [ 76 ]. Similar to other molecules binding to T1, P495 substitutions ( Figure 3 ) were associated with increased resistance to beclabuvir [ 76 , 77 ]. However another T1 RAV A421V, was identified upon treatment of GT1 patients with baclabuvir in a phase 2 trial [ 78 ].…”

Section: Hcv Rdrp As a Target For Daasmentioning

confidence: 59%

“…The mechanism of inhibition for the HCV NNIs appears to vary depending on which of the allosteric sites the inhibitor binds to, although structural studies indicate that most NNIs interfere with conformational changes required for an initiation and elongation competent RdRp [ 65 ]. For instance, benzimidazole and indole derivatives (T1), which have been shown to inhibit the initiation of RNA transcription, had no effect once the RdRp-RNA complex was formed, indicating that these molecules act at a step prior to the formation of a productive RdRp-RNA complex, which is time-dependent [ 77 , 106 , 107 ]. Crystallographic analyses revealed that these molecules prevent the formation of intramolecular contacts between thumb and fingers domain, preventing the formation of a productive RdRp-RNA complex [ 108 ].…”

Section: Mechanism Of Action For Rdrp Nnismentioning

confidence: 99%

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Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

Eltahla

Luciani

White

et al. 2015

Viruses

108

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The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.

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Section: Hcv Rdrp As a Target For Daasmentioning

confidence: 59%

Section: Mechanism Of Action For Rdrp Nnismentioning

confidence: 99%

Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

Eltahla

Luciani

White

et al. 2015

Viruses

108

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“…In general, such compounds inhibit the initiation step of RNA replication [54,55] and not the elongation step. Beclabuvir has been shown to equally inhibit de novo and primer dependent synthesis, 5-75 fold more potently than previously studied compounds [56], thus resulting the most effective thumb site 1 inhibitor of genotype 1 (GT-1) NS5B polymerase to our knowledge [57]. After its binding, beclabuvir inhibits NS5B activity in a time-dependent manner [56], and thus prevents the formation of active replication complexes [58].…”

Section: Mechanism Of Actionmentioning

confidence: 97%

“…In in vitro studies, binding assays with NS5B genetic variants (wild type, L30S and P495L) revealed a two-step, slowbinding mechanism of the drug [56]. In detail, resistance substitutions selected by BCV in genotype 1-based replicons mostly mapped to the NS5B amino acid 495 (P495A/S/ L/T) [52], which therefore can be considered the only clinically relevant resistance variant.…”

Section: Resistant Strainsmentioning

confidence: 99%

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Beclabuvir for the treatment of hepatitis C

Gentile

Zappulo

Buonomo

et al. 2015

Expert Opinion on Investigational Drugs

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The pharmacokinetic, efficacy and tolerability profile of beclabuvir, as well as its barrier to resistance, are very favorable. In particular, the combination of beclabuvir with asunaprevir and daclatasvir achieves very high rates of viral eradication (about 90%) in patients infected with HCV genotype 1, which is the most common genotype worldwide. Therefore, beclabuvir represents a powerful weapon against HCV infection and has to be considered an optimal option in tailored IFN-free combinations.

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Discovery of Beclabuvir: A Potent Allosteric Inhibitor of the Hepatitis C Virus Polymerase

Gentles

2019

Topics in Medicinal Chemistry

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The discovery of beclabuvir occurred through an iterative series of structure-activity relationship studies directed at the optimization of a novel class of indolobenzazepines. Within this research, a strategic decision to abandon a highly potent but physiochemically problematic series in favor of one of lower molecular weight and potency was key in the realization of the program's objectives. Subsequent cycles of analog design incorporating progressive conformational constraints successfully addressed off-target liabilities and identified compounds with improved physiochemical profiles. Ultimately, a class of alkyl-bridged piperazine carboxamides was found to be of particular interest, and from this series, beclabuvir was identified as having superior antiviral, safety, and pharmacokinetic properties. The clinical evaluation of beclabuvir in combination with both the NS5A replication complex inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir in a single, fixed-dose formulation (Ximency) resulted in the approval by the Japanese Pharmaceutical and Food Safety Bureau for its use in the treatment of patients infected with genotype 1 HCV.

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Mechanism of Inhibition for BMS-791325, a Novel Non-nucleoside Inhibitor of Hepatitis C Virus NS5B Polymerase

Cited by 23 publications

References 49 publications

Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

Beclabuvir for the treatment of hepatitis C

Discovery of Beclabuvir: A Potent Allosteric Inhibitor of the Hepatitis C Virus Polymerase

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