Skip to main content
NCBI home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2016 Nov 26;54(12):853–866. doi: 10.1007/s12275-016-6376-1

Inhibitory effects of bee venom and its components against viruses in vitro and in vivo

Md Bashir Uddin 1,2, Byeong-Hoon Lee 1, Chamilani Nikapitiya 1, Jae-Hoon Kim 1, Tae-Hwan Kim 1, Hyun-Cheol Lee 1, Choul Goo Kim 3, Jong-Soo Lee 1,✉, Chul-Joong Kim 1,✉
PMCID: PMC7091203  PMID: 27888461

Abstract

Bee venom (BV) from honey bee (Apis Melifera L.) contains at least 18 pharmacologically active components including melittin (MLT), phospholipase A2 (PLA2), and apamin etc. BV is safe for human treatments dose dependently and proven to possess different healing properties including antibacterial and antiparasitidal properties. Nevertheless, antiviral properties of BV have not well investigated. Hence, we identified the potential antiviral properties of BV and its component against a broad panel of viruses. Co-incubation of non-cytotoxic amounts of BV and MLT, the main component of BV, significantly inhibited the replication of enveloped viruses such as Influenza A virus (PR8), Vesicular Stomatitis Virus (VSV), Respiratory Syncytial Virus (RSV), and Herpes Simplex Virus (HSV). Additionally, BV and MLT also inhibited the replication of non-enveloped viruses such as Enterovirus-71 (EV-71) and Coxsackie Virus (H3). Such antiviral properties were mainly explained by virucidal mechanism. Moreover, MLT protected mice which were challenged with lethal doses of pathogenic influenza A H1N1 viruses. Therefore, these results provides the evidence that BV and MLT could be a potential source as a promising antiviral agent, especially to develop as a broad spectrum antiviral agent.

Keywords: anti-viral activity, bee venom, melittin, virucidal effect

Footnotes

These authors contributed equally to this work.

An erratum to this article is available at http://dx.doi.org/10.1007/s12275-017-0668-y.

Contributor Information

Jong-Soo Lee, Phone: +82-42-821-6753, FAX: +82-42-825-7910, Email: jongsool@cnu.ac.kr.

Chul-Joong Kim, Phone: +82-42-821-6783, FAX: +82-42-825-7910, Email: cjkim@cnu.ac.kr.

References

  1. Arts I.C., Hollman P.C. Polyphenols and disease risk in epidemiologic studies. Am. J. Clin. Nutr. 2005;81:317S–325S. doi: 10.1093/ajcn/81.1.317S. [DOI] [PubMed] [Google Scholar]
  2. Baghian A., Jaynes J., Enright F., Kousoulas K.G. An amphipathic alpha-helical synthetic peptide analogue of melittin inhibits herpes simplex virus-1 (HSV-1)-induced cell fusion and virus spread. Peptides. 1997;18:177–183. doi: 10.1016/S0196-9781(96)00290-2. [DOI] [PubMed] [Google Scholar]
  3. Baghian A., Kousoulas K.G. Role of the Na+, K+ pump in herpes simplex type 1-induced cell fusion: melittin causes specific reversion of syncytial mutants with the syn1 mutation to Syn+ (wild-type) phenotype. Virology. 1993;196:548–556. doi: 10.1006/viro.1993.1510. [DOI] [PubMed] [Google Scholar]
  4. Billingham M.E., Morley J., Hanson J.M., Shipolini R.A., Vernon C.A. Letter: an anti-inflammatory peptide from bee venom. Nature. 1973;245:163–164. doi: 10.1038/245163a0. [DOI] [PubMed] [Google Scholar]
  5. Bouvier N.M., Lowen A.C. Animal models for influenza virus pathogenesis and transmission. Viruses. 2010;2:1530–1563. doi: 10.3390/v20801530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cinatl J., Morgenstern B., Bauer G., Chandra P., Rabenau H., Doerr H.W. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361:2045–2046. doi: 10.1016/S0140-6736(03)13615-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clague M.J., Cherry R.J. Comparison of p25 presequence peptide and melittin. Red blood cell haemolysis and band 3 aggregation. Biochem. J. 1988;252:791–794. doi: 10.1042/bj2520791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coil D.A., Miller A.D. Phosphatidylserine is not the cell surface receptor for vesicular stomatitis virus. J. Virol. 2004;78:10920–10926. doi: 10.1128/JVI.78.20.10920-10926.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cuppoletti J., Abbott A.J. Interaction of melittin with the (Na+ + K+)ATPase: evidence for a melittin-induced conformational change. Arch. Biochem. Biophys. 1990;283:249–257. doi: 10.1016/0003-9861(90)90639-G. [DOI] [PubMed] [Google Scholar]
  10. DeGrado W.F., Musso G.F., Lieber M., Kaiser E.T., Kezdy F.J. Kinetics and mechanism of hemolysis induced by melittin and by a synthetic melittin analogue. Biophys. J. 1982;37:329–338. doi: 10.1016/S0006-3495(82)84681-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dempsey C.E. The actions of melittin on membranes. Biochim. Biophys. Acta. 1990;1031:143–161. doi: 10.1016/0304-4157(90)90006-X. [DOI] [PubMed] [Google Scholar]
  12. Dufourcq J., Faucon J.F., Fourche G., Dasseux J.L., Le Maire M., Gulik-Krzywicki T. Morphological changes of phosphatidylcholine bilayers induced by melittin: vesicularization, fusion, discoidal particles. Biochim. Biophys. Acta. 1986;859:33–48. doi: 10.1016/0005-2736(86)90315-9. [DOI] [PubMed] [Google Scholar]
  13. Dufourc E.J., Smith I.C., Dufourcq J. Molecular details of melittin-induced lysis of phospholipid membranes as revealed by deuterium and phosphorus NMR. Biochemistry. 1986;25:6448–6455. doi: 10.1021/bi00369a016. [DOI] [PubMed] [Google Scholar]
  14. Esser A.F., Bartholomew R.M., Jensen F.C., Muller-Eberhard H.J. Disassembly of viral membranes by complement independent of channel formation. Proc. Natl. Acad. Sci. USA. 1979;76:5843–5847. doi: 10.1073/pnas.76.11.5843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gastaminza P., Kapadia S.B., Chisari F.V. Differential biophysical properties of infectious intracellular and secreted hepatitis C virus particles. J. Virol. 2006;80:11074–11081. doi: 10.1128/JVI.01150-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Habermann E. Bee and wasp venoms. Science. 1972;177:314–322. doi: 10.1126/science.177.4046.314. [DOI] [PubMed] [Google Scholar]
  17. Hwang D.S., Kim S.K., Bae H. Therapeutic effects of bee venom on immunological and neurological diseases. Toxins. 2015;7:2413–2421. doi: 10.3390/toxins7072413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ji H.F., Li X.J., Zhang H.Y. Natural products and drug discovery. Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia? EMBO Rep. 2009;10:194–200. doi: 10.1038/embor.2009.12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kim J.H., Weeratunga P., Kim M.S., Nikapitiya C., Lee B.H., Uddin M.B., Kim T.H., Yoon J.E., Park C., Ma J.Y., et al. Inhibitory effects of an aqueous extract from Cortex Phellodendri on the growth and replication of broad-spectrum of viruses in vitro and in vivo. BMC Complement. Altern. Med. 2016;16:265. doi: 10.1186/s12906-016-1206-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kuchinka E., Seelig J. Interaction of melittin with phosphatidylcholine membranes. Binding isotherm and lipid headgroup conformation. Biochemistry. 1989;28:4216–4221. doi: 10.1021/bi00436a014. [DOI] [PubMed] [Google Scholar]
  21. Lariviere W.R., Melzack R. The bee venom test: a new tonic-pain test. Pain. 1996;66:271–277. doi: 10.1016/0304-3959(96)03075-8. [DOI] [PubMed] [Google Scholar]
  22. Li Q., Zhao Z., Zhou D., Chen Y., Hong W., Cao L., Yang J., Zhang Y., Shi W., Cao Z., et al. Virucidal activity of a scorpion venom peptide variant mucroporin-M1 against measles, SARSCoV and influenza H5N1 viruses. Peptides. 2011;32:1518–1525. doi: 10.1016/j.peptides.2011.05.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lorin C., Combredet C., Labrousse V., Mollet L., Desprès P., Tangy F. A paediatric vaccination vector based on live attenuated measles vaccine. Therapie. 2005;60:227–233. doi: 10.2515/therapie:2005029. [DOI] [PubMed] [Google Scholar]
  24. Mahaney J.E., Thomas D.D. Effects of melittin on molecular dynamics and Ca-ATPase activity in sarcoplasmic reticulum membranes: electron paramagnetic resonance. Biochemistry. 1991;30:7171–7180. doi: 10.1021/bi00243a019. [DOI] [PubMed] [Google Scholar]
  25. Maher S., McClean S. Investigation of the cytotoxicity of eukaryotic and prokaryotic antimicrobial peptides in intestinal epithelial cells in vitro. Biochem. Pharmacol. 2006;71:1289–1298. doi: 10.1016/j.bcp.2006.01.012. [DOI] [PubMed] [Google Scholar]
  26. Marcos J.F., Beachy R.N., Houghten R.A., Blondelle S.E., Pérez-Payá E. Inhibition of a plant virus infection by analogs of melittin. Proc. Natl. Acad. Sci. USA. 1995;92:12466–12469. doi: 10.1073/pnas.92.26.12466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Matanic V.C., Castilla V. Antiviral activity of antimicrobial cationic peptides against Junin virus and herpes simplex virus. Int. J. Antimicrob. Agents. 2004;23:382–389. doi: 10.1016/j.ijantimicag.2003.07.022. [DOI] [PubMed] [Google Scholar]
  28. Park H.J., Lee S.H., Son D.J., Oh K.W., Kim K.H., Song H.S., Kim G.J., Oh G.T., Yoon D.Y., Hong J.T. Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-kappaB through interaction with the p50 subunit. Arthritis Rheum. 2004;50:3504–3515. doi: 10.1002/art.20626. [DOI] [PubMed] [Google Scholar]
  29. Reed L.J., Muench H. A simple method of estimating fifty percent endpoints. Am. J. Hyg. 1938;27:493–497. [Google Scholar]
  30. Scagnolari C., Vicenzi E., Bellomi F., Stillitano M.G., Pinna D., Poli G., Clementi M., Dianzani F., Antonelli G. Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons. Antivir. Ther. 2004;9:1003–1011. [PubMed] [Google Scholar]
  31. Seal B.S., King D.J., Bennett J.D. Characterization of Newcastle disease virus isolates by reverse transcription PCR coupled to direct nucleotide sequencing and development of sequence database for pathotype prediction and molecular epidemiological analysis. J. Clin. Microbiol. 1995;33:2624–2630. doi: 10.1128/jcm.33.10.2624-2630.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Son D.J., Lee J.W., Lee Y.H., Song H.S., Lee C.K., Hong J.T. Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacol. Ther. 2007;115:246–270. doi: 10.1016/j.pharmthera.2007.04.004. [DOI] [PubMed] [Google Scholar]
  33. Strober, W. 2001. Trypan blue exclusion test of cell viability. Curr. Protoc. Immunol. Appendix 3, Appendix 3B. [DOI] [PubMed]
  34. Terwilliger T.C., Weissman L., Eisenberg D. The structure of melittin in the form I crystals and its implication for melittin’s lytic and surface activities. Biophys. J. 1982;37:353–361. doi: 10.1016/S0006-3495(82)84683-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tosteson M.T., Holmes S.J., Razin M., Tosteson D.C. Melittin lysis of red cells. J. Membr. Biol. 1985;87:35–44. doi: 10.1007/BF01870697. [DOI] [PubMed] [Google Scholar]
  36. Triggiani M., Granata F., Frattini A., Marone G. Activation of human inflammatory cells by secreted phospholipases A2. Biochim. Biophys. Acta. 2006;1761:1289–1300. doi: 10.1016/j.bbalip.2006.07.003. [DOI] [PubMed] [Google Scholar]
  37. Wachinger M., Kleinschmidt A., Winder D., von Pechmann N., Ludvigsen A., Neumann M., Holle R., Salmons B., Erfle V., Brack-Werner R. Antimicrobial peptides melittin and cecropin inhibit replication of human immunodeficiency virus 1 by suppressing viral gene expression. J. Gen. Virol. 1998;79:731–740. doi: 10.1099/0022-1317-79-4-731. [DOI] [PubMed] [Google Scholar]
  38. Wachinger M., Saermark T., Erfle V. Influence of amphipathic peptides on the HIV-1 production in persistently infected T lymphoma cells. FEBS Lett. 1992;309:235–241. doi: 10.1016/0014-5793(92)80780-K. [DOI] [PubMed] [Google Scholar]
  39. Weeratunga P., Uddin M.B., Kim M.S., Lee B.H., Kim T.H., Yoon J.E., Ma J.Y., Kim H., Lee J.S. Interferon-mediated antiviral activities of Angelica tenuissima Nakai and its active components. J. Microbiol. 2016;54:57–70. doi: 10.1007/s12275-016-5555-4. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  40. Wen Y.Y., Chang T.Y., Chen S.T., Li C., Liu H.S. Comparative study of enterovirus 71 infection of human cell lines. J. Med. Virol. 2003;70:109–118. doi: 10.1002/jmv.10366. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Microbiology (Seoul, Korea) are provided here courtesy of Nature Publishing Group

RESOURCES