From benzimidazole to indole-5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase. Part 1: Indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons

Beaulieu, Pierre L.; Gillard, James; Jolicoeur, Eric; Duan, Jianmin; Garneau, Michel; Kukolj, George; Poupart, Marc‐André

doi:10.1016/j.bmcl.2011.04.059

Cited by 22 publications

(20 citation statements)

References 21 publications

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“…The thiophene inhibitor failed to inhibit replicons containing GT 2 or 3 NS5B. The indole analog, which targets the alternative GTP binding site on the surface of the thumb domain (2), inhibited the replication of replicons containing NS5B from GT 1 and 3a but was much less active against replicons with GT 2 NS5B polymerase.…”

Section: Genotype Coveragementioning

confidence: 99%

Genotype and Subtype Profiling of PSI-7977 as a Nucleotide Inhibitor of Hepatitis C Virus

Lam¹,

Espiritu²,

Bansal³

et al. 2012

Antimicrob Agents Chemother

222

186

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PSI-7977, a prodrug of 2=-F-2=-C-methyluridine monophosphate, is the purified diastereoisomer of PSI-7851 and is currently being investigated in phase 3 clinical trials for the treatment of hepatitis C. In this study, we profiled the activity of PSI-7977 and its ability to select for resistance using a number of different replicon cells. Results showed that PSI-7977 was active against genotype (GT) 1a, 1b, and 2a (strain JFH-1) replicons and chimeric replicons containing GT 2a (strain J6), 2b, and 3a NS5B polymerase. Cross-resistance studies using GT 1b replicons confirmed that the S282T change conferred resistance to PSI-7977. Subsequently, we evaluated the ability of PSI-7977 to select for resistance using GT 1a, 1b, and 2a (JFH-1) replicon cells. S282T was the common mutation selected among all three genotypes, but while it conferred resistance to PSI-7977 in GT 1a and 1b, JFH-1 GT 2a S282T showed only a very modest shift in 50% effective concentration (EC 50 ) for PSI-7977. Sequence analysis of the JFH-1 NS5B region indicated that additional amino acid changes were selected both prior to and after the emergence of S282T. These include T179A, M289L, I293L, M434T, and H479P. Residues 179, 289, and 293 are located within the finger and palm domains, while 434 and 479 are located on the surface of the thumb domain. Data from the JFH-1 replicon variants showed that amino acid changes within the finger and palm domains together with S282T were required to confer resistance to PSI-7977, while the mutations on the thumb domain serve to enhance the replication capacity of the S282T replicons. Hepatitis C virus (HCV) currently infects more than 170 million people worldwide and is the leading cause of chronic liver disease and liver transplantation in the United States. HCV is a single plus-strand RNA virus about 9.6 kb in genome size and contains one open reading frame that encodes 10 structural and nonstructural (NS) proteins. The structural proteins (core, E1, and E2), which constitute the viral capsid and envelope proteins, are located at the amino terminus, followed by p7, which oligomerizes to form an ion channel critical for viral assembly, and the nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B), which are responsible for viral replication (35). Recently, two antiviral agents have been approved, in combination with pegylated alpha interferon and ribavirin (Peg-IFN/RBV), to treat patients infected with genotype (GT) 1 HCV. Both of these compounds, boceprevir (Victrelis) and telaprevir (Incivek), target the NS3/4A protease and inhibit HCV replication by blocking processing of NS3, NS4A/B, and NS5A/B (25, 33). These treatments showed improvement over Peg-IFN/RBV; however, patients may develop additional side effects corresponding to each of these antiviral compounds (4). Furthermore, viral resistance against these compounds has emerged both in vitro and in vivo as a result of the high genetic diversity of HCV and error-prone nature of the HCV NS5B RNA-dependent RNA polymerase (12). Therefore, research...

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Section: Genotype Coveragementioning

confidence: 99%

Genotype and Subtype Profiling of PSI-7977 as a Nucleotide Inhibitor of Hepatitis C Virus

Lam¹,

Espiritu²,

Bansal³

et al. 2012

Antimicrob Agents Chemother

222

186

View full text Add to dashboard Cite

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“…Such competition is difficult to show conclusively, due to the non-linear effects of VPg concentration in the assay. Alternatively, by binding, they may further the conformational changes in 3D pol needed for elongation, as has been shown for the allosteric, benzimidazole inhibitors of HCV RdRP, which bind within the thumb subdomain 60 . In the absence of VPg, enterovirus 3D pol can fill in the ends of double stranded RNA segments 30 .…”

Section: Discussionmentioning

confidence: 95%

Allosteric inhibitors of Coxsackie virus A24 RNA polymerase

Schein

Rowold

Choi

2016

Bioorganic & Medicinal Chemistry

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Coxsackie virus A24 (CVA24), a causative agent of acute hemorrhagic conjunctivitis, is a prototype of enterovirus (EV) species C. The RNA polymerase (3Dpol) of CVA24 can uridylylate the viral peptide linked to the genome (VPg) from distantly related EV, and is thus, a good model for studying this reaction. Once UMP is bound, VPgpU primes RNA elongation. Structural and mutation data have identified a conserved binding surface for VPg on the RNA polymerase (3Dpol), located about 20Å from the active site. Here, computational docking of over 60,000 small compounds was used to select those with the lowest (best) specific binding energies (BE) for this allosteric site. Compounds with varying structures and low BE were assayed for their effect on formation of VPgU by CVA24-3Dpol. Two compounds with the lowest specific BE for the site inhibited both uridylylation and formation of VPgpolyU at 10–20 µM. These small molecules can be used to probe the role of this allosteric site in polymerase function, and may be the basis for novel antiviral compounds.

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“…Here, the N ‐methylpiperidine moiety seemed to show the better IC 50 of the series (IC 50 = 10 nM for 57c ). Combined with optimized aromatic groups such as benzothiophenes, this structural element surprisingly did not lead to more active derivatives (IC 50 = 17 nM for 57d , Table ) . The X‐ray structures of complexes of RdRp with compound 54c and with an analog of 54d (PDB id: 2BRL and 2BRK) present the binding mode of indoles in the double hydrophobic Thumb Pocket I.…”

Section: Thumb Pocket I Inhibitorsmentioning

confidence: 99%

“…Combined with optimized aromatic groups such as benzothiophenes, this structural element surprisingly did not lead to more active derivatives (IC 50 = 17 nM for 57d, Table XIX). 96,97 The X-ray structures of complexes of RdRp with compound 54c and with an analog of 54d (PDB id: 2BRL and 2BRK) present the binding mode of indoles in the double hydrophobic Thumb Pocket I. The cyclohexyl group binds in the first subpocket, strongly interacting with several hydrophobic amino acids such as Leu425, Ala395, or Ala396.…”

Section: Transposition To the Indole Scaffold And N-acetamide Substitmentioning

confidence: 99%

Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research

et al. 2012

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Hepatitis C is a viral liver infection considered as the major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) possesses a single positive strand RNA genome encoding a polyprotein composed of approximatively 3000 amino acids. The polyprotein is cleaved at multiple sites by cellular and viral proteases to liberate structural and nonstructural (NS) proteins. NS5B, the RNA-dependent RNA polymerase (RdRp), which catalyzes the HCV RNA replication has emerged as an attractive target for the development of specifically targeted antiviral therapy for HCV (DAA, for direct-acting antivirals). In the last 10 years, a growing number of non-nucleoside compounds have been reported as RdRp inhibitors and few are undergoing clinical trials. Over the past 5 years, several reviews were published all describing potentially active molecules. To the best of our knowledge, only one review covers the structure-activity relationships.(1) In this review, we will discuss the reported non-nucleoside molecules acting as RdRp inhibitors according to their chemical class especially focusing on structure-activity relationship aspects among each class of compounds. Thereafter, we will attempt to address the global structural requirements needed for the design of specific inhibitors of RdRp.

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From benzimidazole to indole-5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase. Part 1: Indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons

Cited by 22 publications

References 21 publications

Genotype and Subtype Profiling of PSI-7977 as a Nucleotide Inhibitor of Hepatitis C Virus

Genotype and Subtype Profiling of PSI-7977 as a Nucleotide Inhibitor of Hepatitis C Virus

Allosteric inhibitors of Coxsackie virus A24 RNA polymerase

Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research

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