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Computational Study of HCV p7 Channel: Insight into a New Strategy for HCV Inhibitor Design

  • Beili Ying
  • Shichao Pang
  • Junchen Yang
  • Yang Zhong
  • Jingfang WangEmail author
Original Research Article

Abstract

HCV p7 protein is a cation-selective ion channel, playing an essential role during the life cycle of HCV viruses. To understand the cation-selective mechanism, we constructed a hexameric model in lipid bilayers of HCV p7 protein for HCB JFH-1 strain, genotype 2a. In this structural model, His9 and Val6 were key factors for the HCV cation-selective ion channel. The histidine residues at position 9 in the hexameric model formed a first gate for HCV p7 channel, acting as a selectivity filter for cations. The valines mentioned above formed a second gate for HCV p7 channel, serving as a hydrophobic filter for the dehydrated cations. The binding pocket for the channel blockers, e.g., amantadine and rimantadine, was composed of residues 20–26 in H2 helix and 52–60 in H3 helix in i + 2 monomer. However, the molecular volumes for both amantadine and rimantadine were too small for the binding pocket of HCV p7 channel. Thus, designing a compound similar with rimantadine and having much larger volume would be an effective strategy for discovering inhibitors against HCV p7 channel. To achieve this point, we used rimantadine as a structural template to search ChEMBL database for the candidates employing favorable binding affinities to HCV p7 channel. As a result, six candidates were identified to have potential to be novel inhibitors against HCV p7 channel.

Keywords

Hepatitis C virus P7 channel Structure-based drug design Molecular modeling 

Notes

Acknowledgements

This work was supported by the National Key Research and Development Program of China (no. 2016YFA0500600).

References

  1. 1.
    Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST (2013) Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 57(4):1333–1342CrossRefGoogle Scholar
  2. 2.
    Shepard CW, Finelli L, Alter MJ (2005) Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 5(9):558–567CrossRefGoogle Scholar
  3. 3.
    Lauer GM, Walker BD (2001) Hepatitis C virus infection. N Engl J Med 345(1):41–52CrossRefPubMedGoogle Scholar
  4. 4.
    Seeff LB (1997) Natural history of hepatitis C. Hepatology 26 (3 Suppl 1):21S-28SPubMedGoogle Scholar
  5. 5.
    de Vicente J, Hendricks RT, Smith DB, Fell JB, Fischer J, Spencer SR, Stengel PJ, Mohr P, Robinson JE, Blake JF, Hilgenkamp RK, Yee C, Adjabeng G, Elworthy TR, Tracy J, Chin E, Li J, Wang B, Bamberg JT, Stephenson R, Oshiro C, Harris SF, Ghate M, Leveque V, Najera I, Le Pogam S, Rajyaguru S, Ao-Ieong G, Alexandrova L, Larrabee S, Brandl M, Briggs A, Sukhtankar S, Farrell R, Xu B (2009) Non-nucleoside inhibitors of HCV polymerase NS5B. Part 2: Synthesis and structure-activity relationships of benzothiazine-substituted quinolinediones. Bioorg Med Chem Lett 19(13):3642–3646CrossRefPubMedGoogle Scholar
  6. 6.
    Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle DR 2nd, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, Hamann LG (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465(7294):96–100CrossRefPubMedGoogle Scholar
  7. 7.
    Legrand-Abravanel F, Nicot F, Izopet J (2010) New NS5B polymerase inhibitors for hepatitis C. Expert Opin Investig Drugs 19(8):963–975CrossRefPubMedGoogle Scholar
  8. 8.
    Sofia MJ, Chang W, Furman PA, Mosley RT, Ross BS (2012) Nucleoside, nucleotide, and non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA-polymerase. J Med Chem 55(6):2481–2531CrossRefPubMedGoogle Scholar
  9. 9.
    Zeuzem S (2008) Interferon-based therapy for chronic hepatitis C: current and future perspectives. Nat Clin Pract Gastroenterol Hepatol 5(11):610–622CrossRefPubMedGoogle Scholar
  10. 10.
    Pavlovic D, Neville DC, Argaud O, Blumberg B, Dwek RA, Fischer WB, Zitzmann N (2003) The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives. Proc Natl Acad Sci USA 100(10):6104–6108CrossRefPubMedGoogle Scholar
  11. 11.
    Jones CT, Murray CL, Eastman DK, Tassello J, Rice CM (2007) Hepatitis C virus p7 and NS2 proteins are essential for production of infectious virus. J Virol 81(16):8374–8383CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Steinmann E, Penin F, Kallis S, Patel AH, Bartenschlager R, Pietschmann T (2007) Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions. PLoS Pathog 3(7):e103CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wozniak AL, Griffin S, Rowlands D, Harris M, Yi M, Lemon SM, Weinman SA (2010) Intracellular proton conductance of the hepatitis C virus p7 protein and its contribution to infectious virus production. PLoS Pathog 6(9):e1001087CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    OuYang B, Xie S, Berardi MJ, Zhao X, Dev J, Yu W, Sun B, Chou JJ (2013) Unusual architecture of the p7 channel from hepatitis C virus. Nature 498(7455):521–525CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22(2):195–201CrossRefGoogle Scholar
  16. 16.
    Georgescu RE, Alexov EG, Gunner MR (2002) Combining conformational flexibility and continuum electrostatics for calculating pK(a)s in proteins. Biophys J 83(4):1731–1748CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Laurie AT, Jackson RM (2005) Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinformatics 21(9):1908–1916CrossRefPubMedGoogle Scholar
  18. 18.
    Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461PubMedPubMedCentralGoogle Scholar
  19. 19.
    Case DA, Cheatham TE 3rd, Darden T, Gohlke H, Luo R, Merz Jr KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The Amber biomolecular simulation programs. J Comput Chem 26(16):1668–1688CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Thorner DA, Willett P, Wright PM, Taylor R (1997) Similarity searching in files of three-dimensional chemical structures: representation and searching of molecular electrostatic potentials using field-graphs. J Comput Aided Mol Des 11(2):163–174CrossRefPubMedGoogle Scholar
  21. 21.
    Montserret R, Saint N, Vanbelle C, Salvay AG, Simorre JP, Ebel C, Sapay N, Renisio JG, Bockmann A, Steinmann E, Pietschmann T, Dubuisson J, Chipot C, Penin F (2010) NMR structure and ion channel activity of the p7 protein from hepatitis C virus. J Biol Chem 285(41):31446–31461CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Cook GA, Opella SJ (2011) Secondary structure, dynamics, and architecture of the p7 membrane protein from hepatitis C virus by NMR spectroscopy. Biochim Biophys Acta 1808(6):1448–1453CrossRefPubMedGoogle Scholar
  23. 23.
    Premkumar A, Wilson L, Ewart GD, Gage PW (2004) Cation-selective ion channels formed by p7 of hepatitis C virus are blocked by hexamethylene amiloride. FEBS Lett 557(1–3):99–103CrossRefPubMedGoogle Scholar
  24. 24.
    Griffin SD, Beales LP, Clarke DS, Worsfold O, Evans SD, Jaeger J, Harris MP, Rowlands DJ (2003) The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, amantadine. FEBS Lett 535(1–3):34–38CrossRefPubMedGoogle Scholar
  25. 25.
    Mihm U, Grigorian N, Welsch C, Herrmann E, Kronenberger B, Teuber G, von Wagner M, Hofmann WP, Albrecht M, Lengauer T, Zeuzem S, Sarrazin C (2006) Amino acid variations in hepatitis C virus p7 and sensitivity to antiviral combination therapy with amantadine in chronic hepatitis C. Antivir Ther 11(4):507–519PubMedGoogle Scholar
  26. 26.
    Foster TL, Verow M, Wozniak AL, Bentham MJ, Thompson J, Atkins E, Weinman SA, Fishwick C, Foster R, Harris M, Griffin S (2011) Resistance mutations define specific antiviral effects for inhibitors of the hepatitis C virus p7 ion channel. Hepatology 54(1):79–90CrossRefPubMedGoogle Scholar
  27. 27.
    Castelain S, Bonte D, Penin F, Francois C, Capron D, Dedeurwaerder S, Zawadzki P, Morel V, Wychowski C, Duverlie G (2007) Hepatitis C virus p7 membrane protein quasispecies variability in chronically infected patients treated with interferon and ribavirin, with or without amantadine. J Med Virol 79(2):144–154CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Life SciencesFudan UniversityShanghaiChina
  2. 2.Shanghai Center for Bioinformation TechnologyShanghaiChina
  3. 3.Department of Statistics, School of Mathematical SciencesShanghai Jiao Tong UniversityShanghaiChina
  4. 4.Department of Bioinformatics and Biostatistics, College of Life Science and BiotechnologyShanghai Jiao Tong UniversityShanghaiChina
  5. 5.Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghaiChina

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