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1a/1b subtype profiling of nonnucleoside polymerase inhibitors of hepatitis C virus.

Nyanguile O, Devogelaere B, Vijgen L, Van den Broeck W, Pauwels F, Cummings MD, De Bondt HL, Vos AM, Berke JM, Lenz O, Vandercruyssen G, Vermeiren K, Mostmans W, Dehertogh P, Delouvroy F, Vendeville S, VanDyck K, Dockx K, Cleiren E, Raboisson P, Simmen KA, Fanning GC
J Virol 84 2923-34 (2010)
Cited: 28 times
EuropePMC logo PMID: 20071590

Abstract

The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is an unusually attractive target for drug discovery since it contains five distinct drugable sites. The success of novel antiviral therapies will require nonnucleoside inhibitors to be active in at least patients infected with HCV of subtypes 1a and 1b. Therefore, the genotypic assessment of these agents against clinical isolates derived from genotype 1-infected patients is an important prerequisite for the selection of suitable candidates for clinical development. Here we report the 1a/1b subtype profiling of polymerase inhibitors that bind at each of the four known nonnucleoside binding sites. We show that inhibition of all of the clinical isolates tested is maintained, except for inhibitors that bind at the palm-1 binding site. Subtype coverage varies across chemotypes within this class of inhibitors, and inhibition of genotype 1a improves when hydrophobic contact with the polymerase is increased. We investigated if the polymorphism of the palm-1 binding site is the sole cause of the reduced susceptibility of subtype 1a to inhibition by 1,5-benzodiazepines by using reverse genetics, X-ray crystallography, and surface plasmon resonance studies. We showed Y415F to be a key determinant in conferring resistance on subtype 1a, with this effect being mediated through an inhibitor- and enzyme-bound water molecule. Binding studies revealed that the mechanism of subtype 1a resistance is faster dissociation of the inhibitor from the enzyme.

Reviews - 3hky mentioned but not cited (1)

  1. RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution. Venkataraman S, Prasad BVLS, Selvarajan R. Viruses 10 E76 (2018)

Articles - 3hky mentioned but not cited (5)

  1. A Conserved Pocket in the Dengue Virus Polymerase Identified through Fragment-based Screening. Noble CG, Lim SP, Arora R, Yokokawa F, Nilar S, Seh CC, Wright SK, Benson TE, Smith PW, Shi PY. J Biol Chem 291 8541-8548 (2016)
  2. 1a/1b subtype profiling of nonnucleoside polymerase inhibitors of hepatitis C virus. Nyanguile O, Devogelaere B, Vijgen L, Van den Broeck W, Pauwels F, Cummings MD, De Bondt HL, Vos AM, Berke JM, Lenz O, Vandercruyssen G, Vermeiren K, Mostmans W, Dehertogh P, Delouvroy F, Vendeville S, VanDyck K, Dockx K, Cleiren E, Raboisson P, Simmen KA, Fanning GC. J Virol 84 2923-2934 (2010)
  3. Inhibitors for the hepatitis C virus RNA polymerase explored by SAR with advanced machine learning methods. Weidlich IE, Filippov IV, Brown J, Kaushik-Basu N, Krishnan R, Nicklaus MC, Thorpe IF. Bioorg Med Chem 21 3127-3137 (2013)
  4. Structural Insights into the Binding Modes of Viral RNA-Dependent RNA Polymerases Using a Function-Site Interaction Fingerprint Method for RNA Virus Drug Discovery. Zhao Z, Bourne PE. J Proteome Res 19 4698-4705 (2020)
  5. Accounting for target flexibility and water molecules by docking to ensembles of target structures: the HCV NS5B palm site I inhibitors case study. Barreca ML, Iraci N, Manfroni G, Gaetani R, Guercini C, Sabatini S, Tabarrini O, Cecchetti V. J Chem Inf Model 54 481-497 (2014)


Reviews citing this publication (4)

  1. Anti-HCV drugs in the pipeline. Yang PL, Gao M, Lin K, Liu Q, Villareal VA. Curr Opin Virol 1 607-616 (2011)
  2. Using the Hepatitis C Virus RNA-Dependent RNA Polymerase as a Model to Understand Viral Polymerase Structure, Function and Dynamics. Sesmero E, Thorpe IF. Viruses 7 3974-3994 (2015)
  3. HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy. Chayama K, Hayes CN. Viruses 7 5328-5342 (2015)
  4. Bridging the past and the future of virology: surface plasmon resonance as a powerful tool to investigate virus/host interactions. Rusnati M, Chiodelli P, Bugatti A, Urbinati C. Crit Rev Microbiol 41 238-260 (2015)

Articles citing this publication (18)

  1. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Lam AM, Espiritu C, Bansal S, Micolochick Steuer HM, Niu C, Zennou V, Keilman M, Zhu Y, Lan S, Otto MJ, Furman PA. Antimicrob Agents Chemother 56 3359-3368 (2012)
  2. Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir. Donaldson EF, Harrington PR, O'Rear JJ, Naeger LK. Hepatology 61 56-65 (2015)
  3. New antiviral therapies for chronic hepatitis C. Kanda T, Imazeki F, Yokosuka O. Hepatol Int 4 548-561 (2010)
  4. A highly conserved G-rich consensus sequence in hepatitis C virus core gene represents a new anti-hepatitis C target. Wang SR, Min YQ, Wang JQ, Liu CX, Fu BS, Wu F, Wu LY, Qiao ZX, Song YY, Xu GH, Wu ZG, Huang G, Peng NF, Huang R, Mao WX, Peng S, Chen YQ, Zhu Y, Tian T, Zhang XL, Zhou X. Sci Adv 2 e1501535 (2016)
  5. Thumb inhibitor binding eliminates functionally important dynamics in the hepatitis C virus RNA polymerase. Davis BC, Thorpe IF. Proteins 81 40-52 (2013)
  6. TMC647055, a potent nonnucleoside hepatitis C virus NS5B polymerase inhibitor with cross-genotypic coverage. Devogelaere B, Berke JM, Vijgen L, Dehertogh P, Fransen E, Cleiren E, van der Helm L, Nyanguile O, Tahri A, Amssoms K, Lenz O, Cummings MD, Clayton RF, Vendeville S, Raboisson P, Simmen KA, Fanning GC, Lin TI. Antimicrob Agents Chemother 56 4676-4684 (2012)
  7. Allosteric inhibitors have distinct effects, but also common modes of action, in the HCV polymerase. Davis BC, Brown JA, Thorpe IF. Biophys J 108 1785-1795 (2015)
  8. Hepatitis C virus genotyping using an oligonucleotide microarray based on the NS5B sequence. Gryadunov D, Nicot F, Dubois M, Mikhailovich V, Zasedatelev A, Izopet J. J Clin Microbiol 48 3910-3917 (2010)
  9. High-throughput screening and rapid inhibitor triage using an infectious chimeric Hepatitis C virus. Wichroski MJ, Fang J, Eggers BJ, Rose RE, Mazzucco CE, Pokornowski KA, Baldick CJ, Anthony MN, Dowling CJ, Barber LE, Leet JE, Beno BR, Gerritz SW, Agler ML, Cockett MI, Tenney DJ. PLoS One 7 e42609 (2012)
  10. 10E8-like neutralizing antibodies against HIV-1 induced using a precisely designed conformational peptide as a vaccine prime. Yu Y, Tong P, Li Y, Lu Z, Chen Y. Sci China Life Sci 57 117-127 (2014)
  11. Antiviral activity and mode of action of TMC647078, a novel nucleoside inhibitor of the hepatitis C virus NS5B polymerase. Berke JM, Vijgen L, Lachau-Durand S, Powdrill MH, Rawe S, Sjuvarsson E, Eriksson S, Götte M, Fransen E, Dehertogh P, Van den Eynde C, Leclercq L, Jonckers TH, Raboisson P, Nilsson M, Samuelsson B, Rosenquist Å, Fanning GC, Lin TI. Antimicrob Agents Chemother 55 3812-3820 (2011)
  12. Integrated structure-based activity prediction model of benzothiadiazines on various genotypes of HCV NS5b polymerase (1a, 1b and 4) and its application in the discovery of new derivatives. Ismail MA, Abou El Ella DA, Abouzid KA, Mahmoud AH. Bioorg Med Chem 20 2455-2478 (2012)
  13. A highly selective structure-based virtual screening model of Palm I allosteric inhibitors of HCV Ns5b polymerase enzyme and its application in the discovery and optimization of new analogues. Mahmoud AH, Abou El Ella DA, Ismail MA, Abouzid KA. Eur J Med Chem 57 468-482 (2012)
  14. Effective epitope identification employing phylogenetic, mutational variability, sequence entropy, and correlated mutation analysis targeting NS5B protein of hepatitis C virus: from bioinformatics to therapeutics. Meshram RJ, Gacche RN. J Mol Recognit 28 492-505 (2015)
  15. Molecular simulations to delineate functional conformational transitions in the HCV polymerase. Sesmero E, Brown JA, Thorpe IF. J Comput Chem 38 1125-1137 (2017)
  16. Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845. Vijgen L, Thys K, Vandebosch A, Van Remoortere P, Verloes R, De Meyer S. Virol J 14 101 (2017)
  17. Identification of a common epitope in the sequences of COL4A1 and COL6A1 recognized by monoclonal antibody #141. Sato T, Takano R, Takahara N, Tokunaka K, Saiga K, Tomura A, Sugihara H, Hayashi T, Imamura Y, Morita M. J Biochem 165 85-95 (2019)
  18. Screening of hepatitis C virus inhibitors using genotype 1a HCV replicon cell lines. Robinson M, Tian Y, Pagratis N, Delaney WE. Curr Protoc Microbiol Chapter 17 Unit17.7 (2011)


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