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Planta Med 2014; 80(08/09): 682-687
DOI: 10.1055/s-0034-1368583
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Genistein as Antiviral Drug against HIV Ion Channel

Daniel Sauter
1   Shanghai Research Center for Acupuncture & Meridians, Shanghai, China
2   Institute for Biophysics, JW-Goethe-University, Frankfurt a. M., Germany
4   Present address: University of Copenhagen, Copenhagen, Denmark
,
Silvia Schwarz
1   Shanghai Research Center for Acupuncture & Meridians, Shanghai, China
,
Kai Wang
3   Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
,
Ronghua Zhang
3   Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
,
Bing Sun
3   Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
,
Wolfgang Schwarz
1   Shanghai Research Center for Acupuncture & Meridians, Shanghai, China
2   Institute for Biophysics, JW-Goethe-University, Frankfurt a. M., Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 09. März 2014
revised 14. Mai 2014

accepted 17. Mai 2014

Publikationsdatum:
25. Juni 2014 (online)

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Abstract

Various drugs found in Chinese herbs are well known for their antiviral potency. We have tested several flavonoids with respect to their potency to block the viral protein U of the human immunodeficiency type 1 virus, which is believed to form a cation-permeable ion channel in the infected cell. We used Xenopus oocytes with heterologously expressed viral protein U as model system to test the efficacy of the drugs in voltage-clamp experiments. This method had been demonstrated in the past as a useful tool to screen drugs for their potency in inhibition of ion channel activity. The viral protein U-mediated current could be inhibited by Ba2+ with a K1/2 value of 1.6 mM. Therefore, we determined viral protein U-mediated current as current component blocked by 10 mM Ba2+. We screened several flavonoids with respect to their effects on this current. The flavonols quercetin and kaempferol, and the flavanols (−)epigallochatechin and (−)epichatechin were ineffective. The flavanone naringenin showed at 20 µM slight (about 10 %) inhibition. The most potent drug was the isoflavon genistein which exhibited at 20 µM significant inhibition of about 40 % with a K1/2 value of 81 ± 4 µM. We suggest that viral ion channels, in general, may be a good target for development of antiviral agents, and that, in particular, isoflavons may be candidates for development of drugs targeting viral protein U.

Key words

flavonoids - genistein - HIV-1 - ion channel - virus release
 

  • References

  • 1 Fischer WB, Thiel G, Fink RHA. Viral membrane proteins. Eur Biophys J 2010; 39: 1041-1042
    CrossrefPubMedSuche in Google Scholar
  • 2 Krüger J, Fischer WB. Assembly of viral membrane proteins. J Chem Theory Comput 2009; 5: 2503-2513
    CrossrefPubMedSuche in Google Scholar
  • 3 Wang K, Xie S, Sun B. Viral proteins function as ion channels. Biochim Biophys Acta 2011; 1808: 510-515
    CrossrefPubMedSuche in Google Scholar
  • 4 Fischer WB, Krüger J. Viral channel-forming proteins. Int Rev Cell Mol Biol 2009; 275: 35-63
    PubMedSuche in Google Scholar
  • 5 Liang X, Li ZY. Ion channels as antivirus targets. Virol Sin 2010; 25: 267-280
    CrossrefPubMedSuche in Google Scholar
  • 6 Kelly ML, Cook JA, Brown-Augsburger P, Heinz BA, Smith MC, Pinto LH. Demonstrating the intrinsic ion channel activity of virally encoded proteins. FEBS Lett 2003; 552: 61-67
    CrossrefPubMedSuche in Google Scholar
  • 7 Montal M. Structure−function correlates of Vpu, a membrane protein of HIV-1. FEBS Lett 2003; 552: 47-53
    CrossrefPubMedSuche in Google Scholar
  • 8 Lu W, Zheng BJ, Xu K, Schwarz W, Du LY, Wong CKL, Chen JD, Duan SM, Deubel V, Sun B. Severe acute respiratory syndrome-associated coronavirus 3a protein forms an ion channel and modulates virus release. Proc Natl Acad Sci U S A 2006; 103: 12540-12545
    CrossrefPubMedSuche in Google Scholar
  • 9 Hsu K, Han J, Shinlapawittayatom K, Deschenes I, Marban E. Membrane potential depolarization as a triggering mechanism for Vpu-mediated HIV-1 release. Biophys J 2010; 99: 1718-1725
    CrossrefPubMedSuche in Google Scholar
  • 10 Bour S, Strebel K. The HIV-1 Vpu protein: a multifunctional enhancer of viral particle release. Microbes Infect 2003; 5: 1029-1039
    CrossrefPubMedSuche in Google Scholar
  • 11 McNatt MW, Zang T, Bieniasz PD. Vpu binds directly to tetherin and displaces it from nascent virions. PLoS Pathog 2013; 9: e1003299
    CrossrefPubMedSuche in Google Scholar
  • 12 Neil SJD, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 2008; 451: 425-430
    CrossrefPubMedSuche in Google Scholar
  • 13 Strebel K. HIV-1 Vpu: an ion channel in search of a job. Biochim Biophys Acta 2014; 1838: 1074-1081
    CrossrefPubMedSuche in Google Scholar
  • 14 Schubert U, Ferrer-Montiel AV, Oblatt-Montal M, Henklein P, Strebel K, Montal M. Identification of an ion channel activity of the Vpu transmembrane domain and its involvement in the regulation of virus release from HIV-1-infected cells. FEBS Lett 1996; 398: 12-18
    CrossrefPubMedSuche in Google Scholar
  • 15 Van Damme N, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson MC, Stephens EB, Guatelli J. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe 2008; 3: 245-252
    CrossrefPubMedSuche in Google Scholar
  • 16 Strebel K. HIV-1 Vpu: putting a channel to the TASK. Mol Cell 2004; 14: 150-152
    CrossrefPubMedSuche in Google Scholar
  • 17 Hussain A, Das S, Tanwar C, Jameel S. Oligomerization of the human immunodeficiency virus type 1 (HIV-1) Vpu protein – a genetic, biochemical and biophysical analysis. Virol J 2007; 4: 81
    CrossrefPubMedSuche in Google Scholar
  • 18 Ewart GD, Sutherland T, Gage PW, Cox GB. The Vpu protein of human immunodeficiency virus type 1 forms cation-selective ion channels. J Virol 1996; 70: 7108-7115
    PubMedSuche in Google Scholar
  • 19 Schwarz S, Sauter D, Lu W, Wang K, Sun B, Efferth T, Schwarz W. Coronaviral ion channels as target for Chinese herbal medicine. Forum Immunopathol Dis Therap 2012; 3: 1-13
    PubMedSuche in Google Scholar
  • 20 Tan W, Lu J, Huang M, Li Y, Chen M, Wu G, Gong J, Zhong Z, Xu Z, Dang Y, Guo J, Chen X, Wang Y. Anti-cancer natural products isolated from Chinese medicinal herbs. Chin Med 2011; 6: 27-15
    PubMedSuche in Google Scholar
  • 21 Lown JW. Anthracycline and anthraquinone anticancer agents: Current status and recent developments. Pharmacol Ther 1993; 60: 185-214
    CrossrefPubMedSuche in Google Scholar
  • 22 Naithani R, Huma LC, Holland LE, Shukla D, McCormick DL, Mehta RG, Moriarty RM. Antiviral activity of phytochemicals: A comprehensive review. Mini Rev Med Chem 2008; 8: 1106-1133
    CrossrefPubMedSuche in Google Scholar
  • 23 Mehnert T, Routh A, Judge PJ, Lam YH, Fischer D, Watts A, Fischer WB. Biophysical characterization of Vpu from HIV-1 suggests a channel-pore dualism. Proteins 2008; 70: 1488-1497
    PubMedSuche in Google Scholar
  • 24 Lyu SY, Rhim JY, Park WB. Antiherpetic activities of flavonoids against herpes simplex virus type 1 (HSV-1) and type 2 (SV-2) in vitro. Arch Pharm Res 2005; 28: 1293-1301
    CrossrefPubMedSuche in Google Scholar
  • 25 Mitrocotsa D, Mitaku S, Axarlis S, Harvala C, Malamas M. Evaluation of the antiviral activity of kaempferol and its glycosides against human cytomegalovirus. Planta Med 2000; 66: 377-379
    Thieme ConnectPubMedSuche in Google Scholar
  • 26 Zielonka J, Gebicki J, Grynkiewicz G. Radical scavenging properties of genistein. Free Radic Biol Med 2003; 35: 958-965
    CrossrefPubMedSuche in Google Scholar
  • 27 Andres A, Donovan SM, Kuhlenschmidt MS. Soy isoflavones and virus infections. J Nutr Biochem 2009; 20: 563-569
    CrossrefPubMedSuche in Google Scholar
  • 28 Stantchev TS, Markovic I, Telford WG, Clouse KA, Broder CC. The tyrosine kinase inhibitor genistein blocks HIV-1 infection in primary human macrophages. Virus Res 2007; 123: 178-189
    CrossrefPubMedSuche in Google Scholar
  • 29 Schwarz S, Wang K, Yu W, Sun B, Schwarz W. Emodin inhibits current through SARS-associated coronavirus 3a protein. Antiviral Res 2011; 90: 64-69
    CrossrefPubMedSuche in Google Scholar
  • 30 Schwarz S, Sauter D, Wang K, Zhang RH, Sun B, Karioti A, Bilia AR, Efferth T, Schwarz W. Kaempferol derivatives as antiviral drugs against 3a channel protein of coronavirus. Planta Med 2014; 80: 177-182
    Thieme ConnectPubMedSuche in Google Scholar
  • 31 Lu W, Xu K, Sun B. SARS accessory proteins ORF3a and 9b and their functional analysis. In: Lal SK, editor Molecular biology of the SARS-coronavirus. Berlin, Heidelberg: Springer; 2010: 167-175
    CrossrefSuche in Google Scholar
  • 32 Zhou Y, Frey TK, Yang JJ. Viral calciomics: Interplays between Ca2+ and virus. Cell Calcium 2009; 46: 1-17
    CrossrefPubMedSuche in Google Scholar
  • 33 Kuhl BD, Cheng V, Donahue DA, Sloan RD, Liang C, Wilkinson J, Wainberg MA. The HIV-1 Vpu viroporin inhibitor BIT225 does not affect Vpu-mediated tetherin antagonism. PLoS One 2011; 6: e27660
    CrossrefPubMedSuche in Google Scholar
  • 34 Dumont JN. Oogenesis in Xenopus laevis (Daudin): I. Stages of oocyte development in laboratory maintained animals. J Morphol 1972; 136: 153-180
    CrossrefPubMedSuche in Google Scholar
  • 35 Herrero L, Monroy N, González ME. HIV-1 Vpu protein mediates the transport of potassium in Saccharomyces cerevisiae . Biochemistry 2013; 52: 171-177
    CrossrefPubMedSuche in Google Scholar