Asymmetric Binding to NS5A by Daclatasvir (BMS-790052) and Analogs Suggests Two Novel Modes of HCV Inhibition

Nettles, James H.; Stanton, Richard A.; Broyde, Joshua; Amblard, Franck; Zhang, Hongwang; Zhou, Longhu; Shi, Jiyong; McBrayer, Tamara R.; Whitaker, Tony; Coats, Steven J.; Kohler, James J.; Schinazi, Raymond F.

doi:10.1021/jm501291c

Cited by 46 publications

(55 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As illustrated in Fig. 12, daclatasvir can specifically bind to the HCV nonstruc-tural protein NS5A (282). The exact mechanisms of HCV NS5A drug action remain debated, especially regarding their potential inhibition of the structural stability, dimerization, or subcellular distribution of NS5A (283,284).…”

Section: Hcv Ns5a Inhibitorsmentioning

confidence: 99%

Approved Antiviral Drugs over the Past 50 Years

2016

View full text Add to dashboard Cite

SUMMARYSince the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2′-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2′-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide.

show abstract

Section: Hcv Ns5a Inhibitorsmentioning

confidence: 99%

Approved Antiviral Drugs over the Past 50 Years

2016

View full text Add to dashboard Cite

show abstract

“…A recent report of two additional crystal forms of NS5A domain 1 (gt 1a), together with the previously reported structures (17)(18)(19), suggests that NS5A domain 1 has multiple conformations and a flexibility that may be important for an association of NS5A function and dimers. The ability to model the binding of NS5A compounds in a nonsymmetrical manner may also reflect this property (20). The picomolar potency of DCV toward diverse HCV genotypes coupled with the abundance of the NS5A protein in infected cells supports a polymer-based interaction model of NS5A dimers, in which the binding of DCV to one NS5A dimer influences proximal and distal NS5A dimers that are arranged in a polymeric structure.…”

mentioning

confidence: 96%

Synergistic Activity of Combined NS5A Inhibitors

O’Boyle

Nower

Gao

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

). 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...

show abstract

“…In addition, the serendipitous discovery of NS5A inhibitors as mainstay of all currently approved antiviral combination therapies, represents a beautiful example of investigation in the replicon system that translated to successful clinical use [52]. However, the exact mode of action of NS5A inhibitors as well as of synergistic compounds able to overcome resistance is still unknown [53][54][55][56][57][58]. Advances in these directions may yield new insight into basic principles of RNA and membrane (protein) biology on the one hand and may allow to develop potent antivirals against other positive-strand RNA viruses on the other.…”

Section: Drug Discoverymentioning

confidence: 99%

Future landscape of hepatitis C research – Basic, translational and clinical perspectives

Moradpour

Grakoui

Manns

2016

Journal of Hepatology

View full text Add to dashboard Cite

With the latest all-oral interferon- and ribavirin-free regimens based on direct acting antivirals against the hepatitis C virus (HCV), sustained virological response rates of >90% are achieved, which is equivalent to cure. This has become possible for all genotypes and all subgroups of patients, including many of the most difficult-to-treat populations so far. Since a prophylactic HCV vaccine is not yet available, control of HCV infection will for the time being have to rely on the use of effective and safe antiviral treatments as well as their accessibility and affordability. Different approaches may apply to different parts of the world, eradication of HCV representing a major long-term goal. Whether hepatitis C becomes the first chronic viral infection to be eradicated without a prophylactic vaccine remains to be shown. Here, we briefly summarize advances in the molecular virology of hepatitis C, highlight lessons of biological relevance that were learned through the study of HCV, and its translational and clinical implications. We have also listed selected unsolved challenges, emphasizing that HCV is a unique model and that advances in this direction may yield knowledge of broad biological significance, novel technologies and insights into related important human pathogens.

show abstract

Asymmetric Binding to NS5A by Daclatasvir (BMS-790052) and Analogs Suggests Two Novel Modes of HCV Inhibition

Cited by 46 publications

References 48 publications

Approved Antiviral Drugs over the Past 50 Years

Approved Antiviral Drugs over the Past 50 Years

Synergistic Activity of Combined NS5A Inhibitors

Future landscape of hepatitis C research – Basic, translational and clinical perspectives

Contact Info

Product

Resources

About