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Viral RNA Polymerase Inhibitors

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Viral Genome Replication

Infections by RNA viruses continue to exist as significant public health problems worldwide. In response to the urgent need for safer and more efficacious treatment options against infections caused by RNA viruses, the pharmaceutical and biotechnology industries have devoted significant efforts over the last two decades to discovering and developing new antiviral agents. As the primary viral enzyme responsible for genome replication and transcription, RNA-dependent RNA polymerases (RdRps) emerged early and remained as one of the most promising targets for therapeutic intervention of RNA virus infections. Advances in both basic research and drug discovery technology have resulted in the identification of a significant number of nucleoside (NIs) and non-nucleoside inhibitors (NNIs) of viral RdRps. In this chapter, we will focus our attention on various classes of viral RdRp inhibitors, with main emphases on those of hepatitis C virus (HCV) due to its significant unmet medical need. Recent progress in understanding their mechanism of action, antiviral activity profiles, and emergence of drug resistance mutations will be discussed.

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References

  • Afdhal, N. (2004). Annual Meeting of the American Association for the Study of Liver Diseases. Boston.

    Google Scholar 

  • Ago, H., T. Adachi, et al. (1999). “Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus.” Structure 7(11): 1417–26.

    Article  PubMed  CAS  Google Scholar 

  • Baginski, S. G., D. C. Pevear, et al. (2000). “Mechanism of action of a pestivirus antiviral compound.” Proc Natl Acad Sci USA 97(14): 7981–6.

    Article  PubMed  CAS  Google Scholar 

  • Beaulieu, P. L., M. Bos, et al. (2004a). “Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency.” Bioorg Med Chem Lett 14(4): 967–71.

    Article  PubMed  CAS  Google Scholar 

  • Beaulieu, P. L., M. Bos, et al. (2004b). “Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery and preliminary SAR of benzimidazole derivatives.” Bioorg Med Chem Lett 14(1): 119–24.

    Article  PubMed  CAS  Google Scholar 

  • Biswal, B. K., M. M. Cherney, et al. (2005). “Crystal structures of the RNA-dependent RNA polymerase genotype 2a of hepatitis C virus reveal two conformations and suggest mechanisms of inhibition by non-nucleoside inhibitors.” J Biol Chem 280(18): 18202–10.

    Article  PubMed  CAS  Google Scholar 

  • Biswal, B. K., M. Wang, et al. (2006). “Non-nucleoside inhibitors binding to hepatitis C virus NS5B polymerase reveal a novel mechanism of inhibition.” J Mol Biol 361(1): 33–45.

    Article  PubMed  CAS  Google Scholar 

  • Bressanelli, S., L. Tomei, et al. (1999). “Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus.” Proc Natl Acad Sci USA 96(23): 13034–9.

    Article  PubMed  CAS  Google Scholar 

  • Carroll, S. S. and D. B. Olsen (2006). “Nucleoside analog inhibitors of hepatitis C virus replication.” Infect Disord Drug Targets 6(1): 17–29.

    Article  PubMed  CAS  Google Scholar 

  • Di Marco, S., C. Volpari, et al. (2005). “Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site.” J Biol Chem 280(33): 29765–70.

    Article  PubMed  Google Scholar 

  • Gopalsamy, A., R. Chopra, et al. (2006). “Discovery of proline sulfonamides as potent and selective hepatitis C virus NS5b polymerase inhibitors. Evidence for a new NS5b polymerase binding site.” J Med Chem 49(11): 3052–5.

    Article  PubMed  CAS  Google Scholar 

  • Harper, S., B. Pacini, et al. (2005). “Development and preliminary optimization of indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase.” J Med Chem 48(5): 1314–7.

    Article  PubMed  CAS  Google Scholar 

  • Hayakawa, H., S. Kohgo, et al. (2004). “Potential of 4ʹ-C-substituted nucleosides for the treatment of HIV-1.” Antivir Chem Chemother 15(4): 169–87.

    PubMed  CAS  Google Scholar 

  • Hong, Z., C. E. Cameron, et al. (2001). “A novel mechanism to ensure terminal initiation by hepatitis C virus NS5B polymerase.” Virology 285(1): 6–11.

    Article  PubMed  CAS  Google Scholar 

  • Howe, A. Y., H. Cheng, et al. (2006). “Molecular mechanism of a thumb domain hepatitis C virus nonnucleoside RNA-dependent RNA polymerase inhibitor.” Antimicrob Agents Chemother 50(12): 4103–13.

    Article  PubMed  CAS  Google Scholar 

  • Ishida, T., T. Suzuki, et al. (2006). “Benzimidazole inhibitors of hepatitis C virus NS5B polymerase: identification of 2-[(4-diarylmethoxy)phenyl]-benzimidazole.” Bioorg Med Chem Lett 16(7): 1859–63.

    Article  PubMed  CAS  Google Scholar 

  • Klumpp, K., V. Leveque, et al. (2006). “The novel nucleoside analog R1479 (4ʹ-azidocytidine) is a potent inhibitor of NS5B-dependent RNA synthesis and hepatitis C virus replication in cell culture.” J Biol Chem 281(7): 3793–9.

    Article  PubMed  CAS  Google Scholar 

  • Koch, U., B. Attenni, et al. (2006). “2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: discovery, SAR, modeling, and mutagenesis.” J Med Chem 49(5): 1693–705.

    Article  PubMed  CAS  Google Scholar 

  • Kodama, E. I., S. Kohgo, et al. (2001). “4'-Ethynyl nucleoside analogs: potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro.” Antimicrob Agents Chemother 45(5): 1539–46.

    Article  PubMed  CAS  Google Scholar 

  • Kroll, M., F. Arenzana-Seisdedos, et al. (1999). “The secondary fungal metabolite gliotoxin targets proteolytic activities of the proteasome.” Chem Biol 6(10): 689–98.

    Article  PubMed  CAS  Google Scholar 

  • Kukolj, G., G. A. McGibbon, et al. (2005). “Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase.” J Biol Chem 280(47): 39260–7.

    Article  PubMed  CAS  Google Scholar 

  • Le Pogam, S., W. R. Jiang, et al. (2006a). “In vitro selected Con1 subgenomic replicons resistant to 2ʹ-C-methyl-cytidine or to R1479 show lack of cross resistance.” Virology 351(2): 349–59.

    Article  PubMed  Google Scholar 

  • Le Pogam, S., H. Kang, et al. (2006b). “Selection and characterization of replicon variants dually resistant to thumb- and palm-binding nonnucleoside polymerase inhibitors of the hepatitis C virus.” J Virol 80(12): 6146–54.

    Article  PubMed  Google Scholar 

  • Lesburg, C. A., M. B. Cable, et al. (1999). “Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site.” Nat Struct Biol 6(10): 937–43.

    Article  PubMed  CAS  Google Scholar 

  • Li, H., J. Tatlock, et al. (2006). “Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors.” Bioorg Med Chem Lett 16(18): 4834–8.

    Article  PubMed  CAS  Google Scholar 

  • Lin, C., A. D. Kwong, et al. (2006). “Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3.4A serine protease.” Infect Disord Drug Targets 6(1): 3–16.

    Article  PubMed  CAS  Google Scholar 

  • Liu, Y., W. W. Jiang, et al. (2006). “Mechanistic study of HCV polymerase inhibitors at individual steps of the polymerization reaction.” Biochemistry 45(38): 11312–23.

    Article  PubMed  CAS  Google Scholar 

  • Love, R. A., H. E. Parge, et al. (2003). “Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5B RNA polymerase enzyme.” J Virol 77(13): 7575–81.

    Article  PubMed  CAS  Google Scholar 

  • McKercher, G., P. L. Beaulieu, et al. (2004). “Specific inhibitors of HCV polymerase identified using an NS5B with lower affinity for template/primer substrate.” Nucleic Acids Res 32(2): 422–31.

    Article  PubMed  CAS  Google Scholar 

  • Migliaccio, G., J. E. Tomassini, et al. (2003). “Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro.” J Biol Chem 278(49): 49164–70.

    Article  PubMed  CAS  Google Scholar 

  • Mo, H., L. Lu, et al. (2005). “Mutations conferring resistance to a hepatitis C virus (HCV) RNA-dependent RNA polymerase inhibitor alone or in combination with an HCV serine protease inhibitor in vitro.” Antimicrob Agents Chemother 49(10): 4305–14.

    Article  PubMed  CAS  Google Scholar 

  • Nguyen, T. T., A. T. Gates, et al. (2003). “Resistance profile of a hepatitis C virus RNA-dependent RNA polymerase benzothiadiazine inhibitor.” Antimicrob Agents Chemother 47(11): 3525–30.

    Article  PubMed  CAS  Google Scholar 

  • Olsen, D., M. Davies, et al. (2006). The Nucleoside Inhibitor MK-0608 Mediates Suppression of HCV Replication for >30 Days in Chronically Infected Chimpanzees 46th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco.

    Google Scholar 

  • Olsen, D. B. (2006). Hepatitis C virus resistance to new antivirals 15th International HIV Drug Resistance Workshop. Sitges, Spain.

    Google Scholar 

  • Olsen, D. B., A. B. Eldrup, et al. (2004). “A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties.” Antimicrob Agents Chemother 48(10): 3944–53.

    Article  PubMed  CAS  Google Scholar 

  • Pace, P., E. Nizi, et al. (2004). “The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase.” Bioorg Med Chem Lett 14(12): 3257–61.

    Article  PubMed  CAS  Google Scholar 

  • Paeshuyse, J., P. Leyssen, et al. (2006). “A novel, highly selective inhibitor of pestivirus replication that targets the viral RNA-dependent RNA polymerase.” J Virol 80(1): 149–60.

    Article  PubMed  CAS  Google Scholar 

  • Perrone, P., G. M. Luoni, et al. (2007). “Application of the phosphoramidate ProTide approach to 4ʹ-azidouridine confers sub-micromolar potency versus hepatitis C virus on an inactive nucleoside.” J Med Chem 50(8): 1840–9.

    Article  PubMed  CAS  Google Scholar 

  • Pfefferkorn, J. A., M. L. Greene, et al. (2005a). “Inhibitors of HCV NS5B polymerase. Part 1: Evaluation of the southern region of (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid.” Bioorg Med Chem Lett 15(10): 2481–6.

    Article  PubMed  CAS  Google Scholar 

  • Pfefferkorn, J. A., R. Nugent, et al. (2005b). “Inhibitors of HCV NS5B polymerase. Part 2: Evaluation of the northern region of (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid.” Bioorg Med Chem Lett 15(11): 2812–8.

    Article  PubMed  CAS  Google Scholar 

  • Powers, J. P., D. E. Piper, et al. (2006). “SAR and mode of action of novel non-nucleoside inhibitors of hepatitis C NS5b RNA polymerase.” J Med Chem 49(3): 1034–46.

    Article  PubMed  CAS  Google Scholar 

  • Prakash, T. P., M. Prhavc, et al. (2005). “Synthesis and evaluation of S-acyl-2-thioethyl esters of modified nucleoside 5ʹ-monophosphates as inhibitors of hepatitis C virus RNA replication.” J Med Chem 48(4): 1199–210.

    Article  PubMed  CAS  Google Scholar 

  • Roberts, S., G. Cooksley, et al. (2006). Results of a Phase 1B, Multiple Dose Study of R1626, a Novel Nucleoside Analog Targeting HCV Polymerase in Chronic HCV Genotype 1 Patients. 57th Annual Meeting of the American Association Boston, MA.

    Google Scholar 

  • Rodriguez, P. L. and L. Carrasco (1992). “Gliotoxin: inhibitor of poliovirus RNA synthesis that blocks the viral RNA polymerase 3Dpol.” J Virol 66(4): 1971–6.

    PubMed  CAS  Google Scholar 

  • Shih, I., A. Huang, et al. (2007). 14th International Symposium On Hepatitis C Virus and Related Viruses, Glasgow, UK.

    Google Scholar 

  • Shim, J., G. Larson, et al. (2003). “Canonical 3ʹ-deoxyribonucleotides as a chain terminator for HCV NS5B RNA-dependent RNA polymerase.” Antiviral Res 58(3): 243–51.

    Article  PubMed  CAS  Google Scholar 

  • Slater, M. J., E. M. Amphlett, et al. (2007). “Optimization of Novel Acyl Pyrrolidine Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase Leading to a Development Candidate.” J Med Chem 50(5): 897–900.

    Article  PubMed  CAS  Google Scholar 

  • Smith, D. B., J. A. Martin, et al. (2007). “Design, synthesis, and antiviral properties of 4ʹ-substituted ribonucleosides as inhibitors of hepatitis C virus replication: the discovery of R1479.” Bioorg Med Chem Lett 17(9): 2570–6.

    Article  PubMed  CAS  Google Scholar 

  • Stuyver, L. J., T. R. McBrayer, et al. (2006). “Inhibition of hepatitis C replicon RNA synthesis by beta-D-2ʹ-deoxy-2ʹ-fluoro-2ʹ-C-methylcytidine: a specific inhibitor of hepatitis C virus replication.” Antivir Chem Chemother 17(2): 79–87.

    PubMed  CAS  Google Scholar 

  • Stuyver, L. J., T. R. McBrayer, et al. (2004). “Inhibition of the subgenomic hepatitis C virus replicon in huh-7 cells by 2ʹ-deoxy-2ʹ-fluorocytidine.” Antimicrob Agents Chemother 48(2): 651–4.

    Article  PubMed  CAS  Google Scholar 

  • Summa, V., A. Petrocchi, et al. (2004). “Discovery of alpha, gamma-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase.” J Med Chem 47(1): 14–7.

    Article  PubMed  CAS  Google Scholar 

  • Sun, J. H., J. A. Lemm, et al. (2003). “Specific inhibition of bovine viral diarrhea virus replicase.” J Virol 77(12): 6753–60.

    Article  PubMed  CAS  Google Scholar 

  • Tedesco, R., A. N. Shaw, et al. (2006). “3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.” J Med Chem 49(3): 971–83.

    Article  PubMed  CAS  Google Scholar 

  • Tomassini, J. E., K. Getty, et al. (2005). “Inhibitory effect of 2ʹ-substituted nucleosides on hepatitis C virus replication correlates with metabolic properties in replicon cells.” Antimicrob Agents Chemother 49(5): 2050–8.

    Article  PubMed  CAS  Google Scholar 

  • Tomei, L., S. Altamura, et al. (2003). “Mechanism of action and antiviral activity of benzimidazole-based allosteric inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.” J Virol 77(24): 13225–31.

    Article  PubMed  CAS  Google Scholar 

  • Tomei, L., S. Altamura, et al. (2004). “Characterization of the inhibition of hepatitis C virus RNA replication by nonnucleosides.” J Virol 78(2): 938–46.

    Article  PubMed  CAS  Google Scholar 

  • Wang, M., K. K. Ng, et al. (2003). “Non-nucleoside analogue inhibitors bind to an allosteric site on HCV NS5B polymerase. Crystal structures and mechanism of inhibition.” J Biol Chem 278(11): 9489–95.

    Article  PubMed  CAS  Google Scholar 

  • Yan, S., T. Appleby, et al. (2007). “Isothiazoles as active-site inhibitors of HCV NS5B polymerase.” Bioorg Med Chem Lett 17(1): 28–33.

    Article  PubMed  CAS  Google Scholar 

  • Yan, S., T. Appleby, et al. (2006). “Structure-based design of a novel thiazolone scaffold as HCV NS5B polymerase allosteric inhibitors.” Bioorg Med Chem Lett 16(22): 5888–91.

    Article  PubMed  CAS  Google Scholar 

  • Yang, W., Y. Sun, et al. (2007). “Hepatitis C Virus (HCV) NS5B Nonnucleoside Inhibitors Specifically Block Single-Stranded Viral RNA Synthesis Catalyzed by HCV Replication Complexes In Vitro.” Antimicrob Agents Chemother 51(1): 338–42.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Weidong Zhong .

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Appleby, T., Shih, Ih., Zhong, W. (2009). Viral RNA Polymerase Inhibitors. In: Raney, K., Gotte, M., Cameron, C. (eds) Viral Genome Replication. Springer, Boston, MA. https://doi.org/10.1007/b135974_23

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