HCV NS5A Inhibitors Disrupt Replication Factory Formation: A Novel Mechanism of Antiviral Action

Eyre, Nicholas S.; Beard, Michael R.

doi:10.1053/j.gastro.2014.09.024

Cited by 12 publications

(15 citation statements)

References 24 publications

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“…An additional report of direct binding to NS5A protein of DCV and the related compound ledipasvir also supports the direct association of NS5A RCIs with the NS5A protein (8). Immunomicroscopy analysis indicates that DCV binding results in the apparent disassociation of NS5A from the replication complex, consistent with other evidence that NS5A RCI binding has multiple effects (9)(10)(11)(12)(13).…”

supporting

confidence: 77%

Synergistic Activity of Combined NS5A Inhibitors

O’Boyle

Nower

Gao

et al. 2016

Antimicrob Agents Chemother

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). To extend the characterization of NS5 A synergists, we tested new combinations of DCV and NS5A synergists against genotype (gt) 1 to 6 replicons and gt 1a, 2a, and 3a viruses. The kinetics of inhibition in HCV-infected cells treated with DCV, an NS5A synergist (NS5A-Syn), or a combination of DCV and NS5A-Syn were distinctive. Similar to activity observed clinically, DCV caused a multilog drop in HCV, followed by rebound due to the emergence of resistance. DCV-NS5A-Syn combinations were highly efficient at clearing cells of viruses, in line with the trend seen in replicon studies. The retreatment of resistant viruses that emerged using DCV monotherapy with DCV-NS5A-Syn resulted in a multilog drop and rebound in HCV similar to the initial decline and rebound observed with DCV alone on wild-type (WT) virus. A triple combination of DCV, NS5A-Syn, and a DAA targeting the NS3 or NS5B protein cleared the cells of viruses that are highly resistant to DCV. Our data support the observation that the cooperative interaction of DCV and NS5A-Syn potentiates both the genotype coverage and resistance barrier of DCV, offering an additional DAA option for combination therapy and tools for explorations of NS5A function. Hepatitis C virus (HCV) infections can be effectively cured using combinations of small-molecule direct-acting antivirals (DAAs) with different mechanisms of action. The nonstructural 5A replication complex inhibitor (NS5A RCI) class of compounds represented by daclatasvir (DCV) (BMS-790052, Daklinza; Bristol-Myers Squibb) has activity against genotypes (gts) 1a, 1b, 2a, 3a, 4a, 5a, and 6a and is the most potent class of HCV inhibitor yet described (1-3). NS3 protease inhibitors and NS5B polymerase inhibitors have thus far been the preferred DAA partners for DCV combination therapies (1). Combinations of small-molecule DAAs are required for effective curative oral therapies, because resistant variants existing in the quasispecies population in untreated HCV-infected patients are enriched during monotherapy. To prevent viral breakthrough or relapse and selection of resistant variants, multiple highly effective pangenotypic DAA combination therapies, with NS5A RCIs as the backbone, have been approved or are currently being developed (1, 4, 5).The binding site(s) for NS5A RCIs has been modeled based on biochemical and crystal structure data, implicating at least one site that spans a region between NS5A proteins that associate as dimers (6). Available evidence for NS5A inhibitor binding suggests that NS5A RCIs, such as DCV, bind tightly and specifically to NS5A protein dimers present in infected cells (6).A recent report (7) of DCV binding to Escherichia coli-expressed NS5A protein provided the first direct evidence that DCV binds to NS5A. The authors demonstrated that DCV binding can reduce the affinity of NS5A protein for viral RNA, supporting one potential mechanism of inhibition. An additional report of direct binding to NS5A protein of DCV and the related compound ledipasvir also supports the direct associatio...

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supporting

confidence: 77%

Synergistic Activity of Combined NS5A Inhibitors

O’Boyle

Nower

Gao

et al. 2016

Antimicrob Agents Chemother

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“…DMVs serve as membranous compartment where HCV replication occurs efficiently and safely, protected from cellular RNA sensors and degradation factors [57][58][59]. Interestingly, the Bartenschlager lab and others provided evidence that NS5Ai, like CypI, also prevent the formation of DMVs [55,[60][61]. Importantly, we showed that excepted CypI and NS5Ai, no other classes of anti-HCV agents inhibit the formation of DMVs by HCV [55].…”

Section: Discussionmentioning

confidence: 56%

Characterization of the Anti-HCV Activities of the New Cyclophilin Inhibitor STG-175

Gallay¹,

Chatterji²,

Bobardt³

et al. 2016

Journal of Hepatology

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“…The NS5A phosphoprotein has no known enzymatic activity and its detailed function remains unclear [19]. NS5A inhibitors are thought to interact with NS5A and block formation of the "membranous web" that houses HCV RNA replication.…”

Section: Ns5a Inhibitorsmentioning

confidence: 99%

“…NS5A inhibitors are thought to interact with NS5A and block formation of the "membranous web" that houses HCV RNA replication. They interfere with several functions of NS5A in the HCV life cycle, and disrupt the establishment of replication sites, which in turn prevents continued HVC RNA replication [19]. NS5A inhibitors include daclatasvir, ombitasvir, ledipasvir, elbasvir, and velpatasvir.…”

Section: Ns5a Inhibitorsmentioning

confidence: 99%

A Brief Update on the Treatment of Hepatitis C

Austria¹,

Ninčević²,

Wu³

2017

Update on Hepatitis C

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Hepatitis C virus was discovered nearly 30 years ago, and for the first two decades, treatment was limited to agents with low response rates and substantial side effects. Since the introduction of direct-acting antivirals, there have been rapid advances made toward even higher sustained virologic responses (SVRs) and fewer side effects. This chapter provides a review of the newer agents for treatment of hepatitis C and highlights special populations, including those coinfected with HIV or hepatitis B, previously treated patients, and post-liver transplant patients.

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HCV NS5A Inhibitors Disrupt Replication Factory Formation: A Novel Mechanism of Antiviral Action

Cited by 12 publications

References 24 publications

Synergistic Activity of Combined NS5A Inhibitors

Synergistic Activity of Combined NS5A Inhibitors

Characterization of the Anti-HCV Activities of the New Cyclophilin Inhibitor STG-175

A Brief Update on the Treatment of Hepatitis C

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