Volume 10 Issue 3
Mar.  2019
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Lin Cao, Jizheng Chen, Yaxin Wang, Yuting Yang, Jie Qing, Zihe Rao, Xinwen Chen, Zhiyong Lou. Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy[J]. Protein&Cell, 2019, 10(3): 178-195. doi: 10.1007/s13238-018-0521-z
Citation: Lin Cao, Jizheng Chen, Yaxin Wang, Yuting Yang, Jie Qing, Zihe Rao, Xinwen Chen, Zhiyong Lou. Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy[J]. Protein&Cell, 2019, 10(3): 178-195. doi: 10.1007/s13238-018-0521-z

Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy

doi: 10.1007/s13238-018-0521-z
  • Received Date: 2018-01-05
  • Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance. Viral entry is an essential target step for antiviral development, but FDA-approved HCV entry inhibitor remains exclusive. Here we identify serotonin 2A receptor (5-HT2AR) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy. The silencing of 5-HT2AR and clinically available 5-HT2AR antagonist suppress cell culture-derived HCV (HCVcc) in different liver cells and primary human hepatocytes at late endocytosis process. The mechanism is related to regulate the correct plasma membrane localization of claudin 1 (CLDN1). Moreover, phenoxybenzamine (PBZ), an FDAapproved 5-HT2AR antagonist, inhibits all major HCV genotypes in vitro and displays synergy in combination with clinical used anti-HCV drugs. The impact of PBZ on HCV genotype 2a is documented in immune-competent humanized transgenic mice. Our results not only expand the understanding of HCV entry, but also present a promising target for the invention of HCV entry inhibitor.
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  • [1]
    Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX (1999) Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci USA 96(22):12766– 12771
    [2]
    Baldwin JJ, Christy ME, Denny GH, Habecker CN, Freedman MB, Lyle PA et al (1986) Beta 1-selective adrenoceptor antagonists:examples of the 2-[4-[3-(substituted amino)-2-hydroxypropoxy] phenyl]imidazole class. 2. J Med Chem 29(6):1065–1080 (Epub 1 June 1986)
    [3]
    Bang I, Choi HJ (2015) Structural features of beta2 adrenergic receptor: crystal structures and beyond. Mol Cells 38(2):105–111.https://doi.org/10.14348/molcells.2015.2301 (Epub 30 Dec 2014)
    [4]
    Barnes NM, Sharp T 91999) A review of central 5-HT receptors and their function. Neuropharmacology 38(8):1083–1152 (Epub 16 Aug 1999)
    [5]
    Berg KA, Clarke WP, Chen Y, Ebersole BJ, McKay RD, Maayani S (1994) 5-Hydroxytryptamine type 2A receptors regulate cyclic AMP accumulation in a neuronal cell line by protein kinase C-dependent and calcium/calmodulin-dependent mechanisms.Mol Pharmacol 45(5):826–836 (Epub 1 May 1994)
    [6]
    Brattelid T, Qvigstad E, Lynham JA, Molenaar P, Aass H, Geiran O et al I(2004) Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure. Naunyn Schmiedebergs Arch Pharmacol. 370(3):157–166. https://doi.org/10.1007/s00210-004-0963-0 (Epub 15 Sep 2004).
    [7]
    Chen J, Zhao Y, Zhang C, Chen H, Feng J, Chi X et al (2014)Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice. Cell Res 24(9):1050–1066. https://doi.org/10.1038/cr.2014.116 (Epub 27 Aug 2014)
    [8]
    Cui HK, Qing J, Guo Y, Wang YJ, Cui LJ, He TH et al (2013) Stapled peptide-based membrane fusion inhibitors of hepatitis C virus.Bioorg Med Chem 21(12):3547–3554. https://doi.org/10.1016/j.bmc.2013.02.011 (Epub 16 March 2013)
    [9]
    De Monte A, Courjon J, Anty R, Cua E, Naqvi A, Mondain V et al(2016) Direct-acting antiviral treatment in adults infected with hepatitis C virus: reactivation of hepatitis B virus coinfection as a further challenge. J Clin Virol Off Publ Pan Am Soc Clin Virol 78:27–30. https://doi.org/10.1016/j.jcv.2016.02.026 (Epub 12 March 2016).
    [10]
    Doggrell SA (1995) Increase in affinity and loss of 5-hydroxytryptamine2A-receptor reserve for 5-hydroxytryptamine on the aorta of spontaneously hypertensive rats. J Auton Pharmacol 15(5):371–377 (Epub 1 Jan 1995)
    [11]
    Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wolk B et al (2007) Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446(7137):801–805
    [12]
    Frang H, Cockcroft V, Karskela T, Scheinin M, Marjamaki A (2001)Phenoxybenzamine binding reveals the helical orientation of the third transmembrane domain of adrenergic receptors. J Biol Chem 276(33):31279–31284. https://doi.org/10.1074/jbc.m104167200 (Epub 8 June 2001)
    [13]
    French AD, Fiori JL, Camilli TC, Leotlela PD, O’Connell MP, Frank BP et al (2009) PKC and PKA phosphorylation affect the subcellular localization of claudin-1 in melanoma cells. Int J Med Sci 6(2):93–101 (Epub 24 March 2009)
    [14]
    Gardner JP, Durso RJ, Arrigale RR, Donovan GP, Maddon PJ, Dragic T et al (2003) L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. Proc Natl Acad Sci USA 100(8):4498–4503
    [15]
    Germi R, Crance JM, Garin D, Guimet J, Lortat-Jacob H, Ruigrok RW et al (2002) Cellular glycosaminoglycans and low density lipoprotein receptor are involved in hepatitis C virus adsorption.J Med Virol 68(2):206–215
    [16]
    Gerold G, Meissner F, Bruening J, Welsch K, Perin PM, Baumert TF et al (2015) Quantitative proteomics identifies serum response factor binding protein 1 as a host factor for hepatitis C virus entry.Cell Rep 12(5):864–878
    [17]
    Gondar V, Molina-Jimenez F, Hishiki T, Garcia-Buey L, Koutsoudakis G, Shimotohno K et al (2015) Apolipoprotein E, but not apolipoprotein B, is essential for efficient cell-to-cell transmission of hepatitis C virus. J Virol 89(19):9962–9973. https://doi.org/10. 1128/jvi.00577-15 (Epub 24 July 2015)
    [18]
    Han Q, Xu C, Wu C, Zhu W, Yang R, Chen X (2009) Compensatory mutations in NS3 and NS5A proteins enhance the virus production capability of hepatitis C reporter virus. Virus Res 145(1):63–73.https://doi.org/10.1016/j.virusres.2009.06.005 (Epub 23 June 2009)
    [19]
    Hao W, Herlihy KJ, Zhang NJ, Fuhrman SA, Doan C, Patick AK et al(2007) Development of a novel dicistronic reporter-selectable hepatitis C virus replicon suitable for high-throughput inhibitor screening. Antimicrob Agents Chemother 51(1):95–102.https://doi.org/10.1128/aac.01008-06
    [20]
    Harris HJ, Davis C, Mullins JG, Hu K, Goodall M, Farquhar MJ et al(2010) Claudin association with CD81 defines hepatitis C virus entry. J Biol Chem 285(27):21092–21102. https://doi.org/10.1074/jbc.m110.104836 (Epub 9 April 2010)
    [21]
    He S, Lin B, Chu V, Hu Z, Hu X, Xiao J et al (2015) Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection. Sci Transl Med 7(282):282ra49. https://doi.org/10.1126/scitranslmed.3010286 (Epub 10 April 2015).
    [22]
    Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71(4):533–554 (Epub 13 March 2002)
    [23]
    Lindenbach BD, Rice CM (2013) The ins and outs of hepatitis C virus entry and assembly. Nat Rev Microbiol 11(10):688–700
    [24]
    Liu S, McCormick KD, Zhao W, Zhao T, Fan D, Wang T (2012) Human apolipoprotein E peptides inhibit hepatitis C virus entry by blocking virus binding. Hepatology 56(2):484–491
    [25]
    Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285(5424):110–113
    [26]
    Lozach PY, Lortat-Jacob H, de Lacroix de Lavalette A, Staropoli I, Foung S, Amara A et al (2003) DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2.J Biol Chem 278(22):20358–20366
    [27]
    Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I, Zona L et al(2011) EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med 17(5):589–595
    [28]
    Mahe C, Loetscher E, Feuerbach D, Muller W, Seiler MP, Schoeffter P (2004) Differential inverse agonist efficacies of SB-258719, SB-258741 and SB-269970 at human recombinant serotonin 5-HT7 receptors. Eur J Pharmacol 495(2–3):97–102. https://doi.org/10.1016/j.ejphar.2004.05.033 (Epub 14 July 2004)
    [29]
    Martin DN, Uprichard SL (2013) Identification of transferrin receptor 1 as a hepatitis C virus entry factor. Proc Natl Acad Sci USA 110(26):10777–10782
    [30]
    Ozaras R, Yemisen M, Balkan Ⅱ (2013) Current and future therapies for hepatitis C virus infection. N Engl J Med 369(7):679. https://doi.org/10.1056/nejmc1307589#sa1 (Epub 16 Aug 2013)
    [31]
    Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R et al(1998) Binding of hepatitis C virus to CD81. Science 282(5390):938–941
    [32]
    Ploss A, Evans MJ, Gaysinskaya VA, Panis M, You H, de Jong YP et al (2009) Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457(7231):882–886
    [33]
    Popoli M (2009) Agomelatine: innovative pharmacological approach in depression. CNS Drugs 23(Suppl 2):27–34 https://doi.org/10.2165/11318640-000000000-00000 (Epub 4 Sep 2009)
    [34]
    Prichard MN, Shipman C Jr (1990) A three-dimensional model to analyze drug–drug interactions. Antiviral Res 14(4–5):181–205
    [35]
    Qing J, Luo R, Wang Y, Nong J, Wu M, Shao Yet al (2016) Resistance analysis and characterization of NITD008 as an adenosine analog inhibitor against hepatitis C virus. Antiviral Res 126:43–54. https://doi.org/10.1016/j.antiviral.2015.12.010 (Epub 3 Jan 2016)
    [36]
    Raote I, Bhattacharyya S, Panicker MM (2013) Functional selectivity in serotonin receptor 2A (5-HT2A) endocytosis, recycling, and phosphorylation. Mol Pharmacol 83(1):42–50. https://doi.org/10. 1124/mol.112.078626 (Epub 5 Oct 2012)
    [37]
    Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW et al (2001) Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 92(2–3):179–212(Epub 28 March 2002)
    [38]
    Sainz B Jr, Barretto N, Martin DN, Hiraga N, Imamura M, Hussain S et al (2012) Identification of the Niemann–Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. Nat Med 18(2):281–285
    [39]
    Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G et al (2002) The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J 21(19):5017–5025
    [40]
    Shukla P, Faulk KN, Emerson SU (2010) The entire core protein of HCV JFH1 is required for efficient formation of infectious JFH1 pseudoparticles. J Med Virol 82(5):783–790. https://doi.org/10.1002/jmv.21660 (Epub 26 March 2010)
    [41]
    Tamir H, Hsiung SC, Yu PY, Liu KP, Adlersberg M, Nunez EA et al(1992) Serotonergic signalling between thyroid cells: protein kinase C and 5-HT2 receptors in the secretion and action of serotonin. Synapse (N Y, NY) 12(2):155–168. https://doi.org/10.1002/syn.890120209 (Epub 1 Oct 1992)
    [42]
    Tsukagoshi S (1999) Pharmacokinetics of azasetron (Serotone), a selective 5-HT3 receptor antagonist. Gan To Kagaku Ryoho 26(7):1001–1008 (Epub 9 July 1999)
    [43]
    Ujino S, Nishitsuji H, Hishiki T, Sugiyama K, Takaku H, Shimotohno K (2016) Hepatitis C virus utilizes VLDLR as a novel entry pathway. Proc Natl Acad Sci USA 113(1):188–193
    [44]
    Upton N, Chuang TT, Hunter AJ, Virley DJ (2008) 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics 5(3):458–469. https://doi.org/10. 1016/j.nurt.2008.05.008 (Epub 16 July 2008)
    [45]
    Vacher B, Funes P, Chopin P, Cussac D, Heusler P, Tourette A et al(2010) Rigid analogues of the alpha2-adrenergic blocker atipamezole: small changes, big consequences. J Med Chem 53(19):6986– 6995 https://doi.org/10.1021/jm1006269 (Epub 3 Sep 2010)
    [46]
    van den Meiracker AH, Man in ’t Veld AJ, Fischberg DJ, Molinoff PB, van Eck HJ, Boomsma F et al (1988) Acute and long-term effects of acebutolol on systemic and renal hemodynamics, body fluid volumes, catecholamines, active renin, aldosterone, and lymphocyte beta-adrenoceptor density. J Cardiovasc Pharmacol 11(4):413–423 (Epub 1 April 1988)
    [47]
    Wang C, Ji D, Chen J, Shao Q, Li B, Liu J et al (2017) Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents.Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 15(1):132–136. https://doi.org/10.1016/j.cgh.2016.06.023(Epub 10 July 2016)
    [48]
    Webster DP, Klenerman P, Dusheiko GM (2015) Hepatitis C. Lancet 385(9973):1124–1135
    [49]
    Weinstock LM, Mulvey DM, Tull R (1976) Synthesis of the betaadrenergic blocking agent timolol from optically active precursors.J Org Chem 41(19):3121–3124 (Epub 17 Sep 1976)
    [50]
    Wilde MI, Fitton A, McTavish D (1993) Alfuzosin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in benign prostatic hyperplasia. Drugs 45(3):410– 429 (Epub 1 March 1993)
    [51]
    Zhong J, Gastaminza P, Chung J, Stamataki Z, Isogawa M, Cheng G et al (2006) Persistent hepatitis C virus infection in vitro:coevolution of virus and host. J Virol 80(22):11082–11093
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