Syntheses and initial evaluation of a series of indolo-fused heterocyclic inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus

Zheng, Xiaofan; Hudyma, Thomas W.; Martin, Scott; Bergstrom, Carl P.; Ding, Min; He, Feng; Romine, J.; Poss, Michael A.; Kadow, John F.; Chang, Chong-Hwan; Wan, John; Witmer, Mark R.; Morin, Paul E.; Camac, Daniel M.; Sheriff, S.; Beno, Brett R.; Rigat, Karen; Wang, Ying-Kai; Fridell, Robert A.; Lemm, Julie A.; Qiu, Dike; Liu, Mengping; Voss, Stacey; Pelosi, Lenore A.; Roberts, Susan B.; Gao, Min; Knipe, Jay O.; Gentles, Robert G.

doi:10.1016/j.bmcl.2011.03.067

Cited by 37 publications

(37 citation statements)

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“…Sofosbuvir and mericitabine treatment rarely select for resistant variants, identified as carrying substitutions S282T and/or L159F/L320F in NS5B. [6]–[9] There are also several investigational non-nucleoside NS5B inhibitors (NNIs) including ABT-072, ABT 333 and setrobuvir which bind to the Palm I allosteric domain, [10], [11] BMS-791325 [12] and BI207127 which bind to the Thumb I site [13], and VX-222 and filibuvir which bind to the Thumb II site. [14], [15] In contrast to NI-resistant NS5B variants, NNI-resistant variants emerge rapidly in vitro and in vivo .…”

Section: Introductionmentioning

confidence: 99%

Similar Prevalence of Low-Abundance Drug-Resistant Variants in Treatment-Naive Patients with Genotype 1a and 1b Hepatitis C Virus Infections as Determined by Ultradeep Pyrosequencing

Margeridon-Thermet

Pogam

et al. 2014

PLoS ONE

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Background and ObjectivesHepatitis C virus (HCV) variants that confer resistance to direct-acting-antiviral agents (DAA) have been detected by standard sequencing technology in genotype (G) 1 viruses from DAA-naive patients. It has recently been shown that virological response rates are higher and breakthrough rates are lower in G1b infected patients than in G1a infected patients treated with certain classes of HCV DAAs. It is not known whether this corresponds to a difference in the composition of G1a and G1b HCV quasispecies in regards to the proportion of naturally occurring DAA-resistant variants before treatment.MethodsWe used ultradeep pyrosequencing to determine the prevalence of low-abundance (<25% of the sequence reads) DAA-resistant variants in 191 NS3 and 116 NS5B isolates from 208 DAA-naive G1-infected patients.ResultsA total of 3.5 million high-quality reads of ≥200 nucleotides were generated. The median coverage depth was 4150x and 4470x per NS3 and NS5B amplicon, respectively. Both G1a and G1b populations showed Shannon entropy distributions, with no difference between G1a and G1b in NS3 or NS5B region at the nucleotide level. A higher number of substitutions that confer resistance to protease inhibitors were observed in G1a isolates (mainly at amino acid 80 of the NS3 region). The prevalence of amino acid substitutions that confer resistance to NS5B non-nucleoside inhibitors was similar in G1a and G1b isolates. The NS5B S282T variant, which confers resistance to the polymerase inhibitors mericitabine and sofosbuvir, was not detected in any sample.ConclusionThe quasispecies genetic diversity and prevalence of DAA-resistant variants was similar in G1a and G1b isolates and in both NS3 and NS5B regions, suggesting that this is not a determinant for the higher level of DAA resistance observed across G1a HCV infected patients upon treatment.

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Section: Introductionmentioning

confidence: 99%

Similar Prevalence of Low-Abundance Drug-Resistant Variants in Treatment-Naive Patients with Genotype 1a and 1b Hepatitis C Virus Infections as Determined by Ultradeep Pyrosequencing

Margeridon-Thermet

Pogam

et al. 2014

PLoS ONE

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“…In practice, resistance has emerged to all small-molecule inhibitors of HCV tested as monotherapy except some nucleoside-nucleotide NS5B inhibitors. Resistance mutations have been identified both in vitro and in vivo upon treatment with nearly all inhibitors of HCV serine protease, NS5A, or allo-steric RNA polymerase inhibitors advanced to date (3,19,22,23,24,30,36,38,51,52,57,60,62), with good correlation observed between resistance emergence in the replicon system and in vivo. Recent literature indicates that treatment with combinations of non-cross-resistant inhibitors not only improves antiviral activity during treatment but also suppresses the posttreatment viral rebound often associated with monotherapy (19,21,26).…”

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confidence: 99%

Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

Pelosi

Voss

Liu

et al. 2012

Antimicrob Agents Chemother

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Three hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additivesynergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic. H epatitis C virus (HCV) is a positive-stranded RNA virus in theFlaviviridae family of enveloped virions which affects an estimated 170 million people worldwide and is the major cause of chronic hepatitis. Currently, approximately 50% of patients infected with genotype 1 (gt 1), the most prevalent form of the virus, fail to achieve a sustained reduction in viral load with therapy employing pegylated alpha interferon (IFN-␣) plus ribavirin (alfa/RBV) (52,54,56). A substantial fraction (20%) of chronically infected patients develop serious progressive liver disease, including cirrhosis or hepatocellular carcinoma. alfa/RBV treatment is associated with a high incidence (Ͼ30%) of adverse effects, some of which are of sufficient severity to cause patients to discontinue therapy (56). Despite the recent approval of two new direct-acting antiviral agents (DAAs), boceprevir and telaprevir, for use in combination with alfa/RBV (18, 47), their use may be limited by poor efficacy in some patient populations, inconvenient 3-times-daily dosing of the DAA, and association with side effects, including anemia, rash, and gastrointestinal effects, in addition to the well-documented spectrum of adverse effects associated with alfa/RBV. Although addition of these DAAs to the standard of care for HCV represents a significant i...

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“…The following targets were shortlisted from the above procedure for sporolides A and B. The 3D structure of the target proteins, μ ‐opioid receptor (PDB ID: 2IQO) , HIV‐1 chain A (PDB ID: 3T19) , adenosine A3 receptor (PDB ID: 1OEA) , hepatitis C virus NS5B RNA‐dependent RNA polymerase (PDB ID: 3Q0Z) , and voltage‐gated L‐type calcium channel α ‐1C subunit/calcium channel α 2/Δ subunit 1 (PDB ID: 3OXQ), were downloaded from Protein Data Bank. The structure of equilibrative nucleoside transporter 1, endothelin receptor ET‐A, and oxytocin receptor was modeled using I‐TASSER server (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Biological Activity of Sporolides A and B from Salinispora tropica: in silico Target Prediction Using Ligand‐Based Pharmacophore Mapping and in vitro activity Validation on HIV‐1 Reverse Transcriptase

et al. 2014

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Sporolides A and B are novel polycyclic macrolides from the obligate marine actinomycetes, Salinispora tropica. The unique and novel structure of sporolides makes them interesting candidates for targeting diverse biological activities. Biological target prediction of sporolides was carried out using ligand-based pharmacophore screening against known inhibitors and drugs. Validation of pharmacophore screening was carried out for the identified hits. New biological targets predicted for sporolides using this method were HIV-1 reverse transcriptase, adenosine A3 receptor, endothelin receptor ET-A, oxytocin receptor, voltage-gated L-type calcium channel α-1C subunit/calcium channel α/Δ subunit 1. Drug-likeness properties were predicted for the selected compounds using QikProp module. Sporolides A and B showed maximum docking score with HIV-1 reverse transcriptase. Structural interaction fingerprints analysis indicated similar binding pattern of the sporolides with the HIV-1 reverse transcriptase. Sporolide B exhibited good inhibitory activity against HIV-1 reverse transcriptase in in vitro fluorescent assay.

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Syntheses and initial evaluation of a series of indolo-fused heterocyclic inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus

Cited by 37 publications

References 16 publications

Similar Prevalence of Low-Abundance Drug-Resistant Variants in Treatment-Naive Patients with Genotype 1a and 1b Hepatitis C Virus Infections as Determined by Ultradeep Pyrosequencing

Similar Prevalence of Low-Abundance Drug-Resistant Variants in Treatment-Naive Patients with Genotype 1a and 1b Hepatitis C Virus Infections as Determined by Ultradeep Pyrosequencing

Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

Biological Activity of Sporolides A and B from Salinispora tropica: in silico Target Prediction Using Ligand‐Based Pharmacophore Mapping and in vitro activity Validation on HIV‐1 Reverse Transcriptase

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