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The Natural Product Eugenol Is an Inhibitor of the Ebola Virus In Vitro

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Abstract

Purpose

Since the 2014 Ebola virus (EBOV) outbreak in West Africa there has been considerable effort towards developing drugs to treat Ebola virus disease and yet to date there is no FDA approved treatment. This is important as at the time of writing this manuscript there is an ongoing outbreak in the Democratic Republic of the Congo which has killed over 1000.

Methods

We have evaluated a small number of natural products, some of which had shown antiviral activity against other pathogens. This is exemplified with eugenol, which is found in high concentrations in multiple essential oils, and has shown antiviral activity against feline calicivirus, tomato yellow leaf curl virus, Influenza A virus, Herpes Simplex virus type 1 and 2, and four airborne phages.

Results

Four compounds possessed EC50 values less than or equal to 11 μM. Of these, eugenol, had an EC50 of 1.3 μM against EBOV and is present in several plants including clove, cinnamon, basil and bay. Eugenol is much smaller and structurally unlike any compound that has been previously identified as an inhibitor of EBOV, therefore it may provide new mechanistic insights.

Conclusion

This compound is readily accessible in bulk quantities, is inexpensive, and has a long history of human consumption, which endorses the idea for further assessment as an antiviral therapeutic. This work also suggests that a more exhaustive assessment of natural product libraries against EBOV and other viruses is warranted to improve our ability to identify compounds that are so distinct from FDA approved drugs.

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References

  1. Spainhour CB. Naturla products. In: Gad SC, editor. Drug discovery handbook. Hoboken: John Wiley and Sons; 2005. p. 11–72.

    Chapter  Google Scholar 

  2. Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016;79(3):629–61.

    Article  CAS  PubMed  Google Scholar 

  3. Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 2012;75(3):311–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo). 1975;28(10):721–6.

    Article  CAS  Google Scholar 

  5. Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev. 2001;65(2):232–60 second page, table of contents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li R. Marinopyrroles: unique drug discoveries based on marine natural products. Med Res Rev. 2016;36(1):169–89.

    Article  CAS  PubMed  Google Scholar 

  7. Mayer AM, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, et al. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol Sci. 2010;31(6):255–65.

    Article  CAS  PubMed  Google Scholar 

  8. Kaiser R. Meaningful scents around the world. Zurich: Wiley, VCH; 2006.

  9. Tokunaga T, Sugawara H, Tadano C, Muro M. Effect of stimulation of cold receptors with menthol on EMG activity of quadriceps muscle during low load contraction. Somatosens Mot Res. 2017;34(2):85–91.

    Article  PubMed  Google Scholar 

  10. Suchodolski J, Feder-Kubis J, Krasowska A. Antifungal activity of ionic liquids based on (−)-menthol: a mechanism study. Microbiol Res. 2017;197:56–64.

    Article  CAS  PubMed  Google Scholar 

  11. Wondergem R, Bartley JW. Menthol increases human glioblastoma intracellular Ca2+, BK channel activity and cell migration. J Biomed Sci. 2009;16:90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Park EJ, Kim SH, Kim BJ, Kim SY, So I, Jeon JH. Menthol enhances an Antiproliferative activity of 1alpha,25-Dihydroxyvitamin D(3) in LNCaP cells. J Clin Biochem Nutr. 2009;44(2):125–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Watt EE, Betts BA, Kotey FO, Humbert DJ, Griffith TN, Kelly EW, et al. Menthol shares general anesthetic activity and sites of action on the GABA(a) receptor with the intravenous agent, propofol. Eur J Pharmacol. 2008;590(1–3):120–6.

    Article  CAS  PubMed  Google Scholar 

  14. Shahverdi AR, Fazeli MR, Rafii F, Kakavand M, Jamalifar H, Hamedi J. Inhibition of nitrofurantoin reduction by menthol leads to enhanced antimicrobial activity. J Chemother. 2003;15(5):449–53.

    Article  CAS  PubMed  Google Scholar 

  15. Juergens UR, Stober M, Vetter H. The anti-inflammatory activity of L-menthol compared to mint oil in human monocytes in vitro: a novel perspective for its therapeutic use in inflammatory diseases. Eur J Med Res. 1998;3(12):539–45.

    CAS  PubMed  Google Scholar 

  16. Zimmermann M, Preac-Mursic V. In vitro activity of taurolidine, chlorophenol-camphor-menthol and chlorhexidine against oral pathogenic microorganisms. Arzneimittelforschung. 1992;42(9):1157–9.

    CAS  PubMed  Google Scholar 

  17. CDC. 2014 ebola outbreak in West Africa - case counts 2016. Available from: http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/case-counts.html. Accessed 3 may 2019.

  18. Hoenen T, Feldmann H. Reverse genetics systems as tools for the development of novel therapies against filoviruses. Expert Rev Anti-Infect Ther. 2014;12(10):1253–63.

    Article  CAS  PubMed  Google Scholar 

  19. Johansen LM, Brannan JM, Delos SE, Shoemaker CJ, Stossel A, Lear C, et al. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Sci Transl Med. 2013;5(190):190ra179–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Madrid PB, Chopra S, Manger ID, Gilfillan L, Keepers TR, Shurtleff AC, Green CE, Iyer LV, Dilks HH, Davey RA, Kolokoltsov AA, Carrion R, Jr., Patterson JL, Bavari S, Panchal RG, Warren TK, Wells JB, Moos WH, Burke RL, Tanga MJ. A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS One 2013;8(4):e60579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Johansen LM, DeWald LE, Shoemaker CJ, Hoffstrom BG, Lear-Rooney CM, Stossel A, et al. A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity. Sci Transl Med. 2015;7(290):290ra289.

    Article  PubMed  CAS  Google Scholar 

  22. Kouznetsova J, Sun W, Martinez-Romero C, Tawa G, Shinn P, Chen CZ, et al. Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Emerg Microbes Infect. 2014;3(12):e84.

    Article  CAS  Google Scholar 

  23. Edwards MR, Pietzsch C, Vausselin T, Shaw ML, Bukreyev A, Basler CF. High-throughput Minigenome system for identifying small-molecule inhibitors of Ebola virus replication. ACS Infect Dis. 2015;1(8):380–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cheng H, Lear-Rooney CM, Johansen L, Varhegyi E, Chen ZW, Olinger GG, et al. Inhibition of Ebola and Marburg virus entry by G protein-coupled receptor antagonists. J Virol. 2015;89(19):9932–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Anantpadma M, Kouznetsova J, Wang H, Huang R, Kolokoltsov A, Guha R, et al. Large-scale screening and identification of novel Ebola virus and Marburg virus entry inhibitors. Antimicrob Agents Chemother. 2016;60(8):4471–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang Y, Cui R, Li G, Gao Q, Yuan S, Altmeyer R, et al. Teicoplanin inhibits Ebola pseudovirus infection in cell culture. Antivir Res. 2016;125:1–7.

    Article  CAS  PubMed  Google Scholar 

  27. Luthra P, Liang J, Pietzsch CA, Khadka S, Edwards MR, Wei S, et al. A high throughput screen identifies benzoquinoline compounds as inhibitors of Ebola virus replication. Antivir Res. 2018;150:193–201.

    Article  CAS  PubMed  Google Scholar 

  28. Litterman NK, Lipinski CA, Ekins S. Small molecules with antiviral activity against the Ebola virus. F1000Res. 2015;4:38.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Picazo E, Giordanetto F. Small molecule inhibitors of ebola virus infection. Drug Discov Today. 2014;20:277–86.

    Article  PubMed  CAS  Google Scholar 

  30. Basu A, Mills DM, Mitchell D, Ndungo E, Williams JD, Herbert AS, et al. Novel small molecule entry inhibitors of Ebola virus. J Infect Dis. 2015;212(Suppl 2):S425–34.

    Article  CAS  Google Scholar 

  31. Long J, Wright E, Molesti E, Temperton N, Barclay W. Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry. F1000Res. 2015;4:30.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. Ebola virus entry requires the cholesterol transporter Niemann-pick C1. Nature. 2011;477(7364):340–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rhein BA, Maury WJ. Ebola virus entry into host cells: identifying therapeutic strategies. Curr Clin Microbiol Rep. 2015;2(3):115–24.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ekins S, Freundlich JS, Clark AM, Anantpadma M, Davey RA. P. M. machine learning models identify molecules active against the Ebola virus in vitro. F1000Res. 2016;4:1091.

    Article  Google Scholar 

  35. Ekins S, Lingerfelt MA, Comer JE, Freiberg AN, Mirsalis JC, O’Loughlin K, et al. Efficacy of Tilorone Dihydrochloride against Ebola virus infection. Antimicrob Agents Chemother. 2017;In Press;62.

  36. Bai JPF, Hsu CW. Drug repurposing for Ebola virus disease: principles of consideration and the animal rule. J Pharm Sci. 2018. https://doi.org/10.1016/j.xphs.2018.1009.1010 Epub ahead of print.

  37. Murray MF. Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Clin Infect Dis. 2003;36(4):453–60.

    Article  CAS  PubMed  Google Scholar 

  38. Andrade-Ochoa S, Nevarez-Moorillon GV, Sanchez-Torres LE, Villanueva-Garcia M, Sanchez-Ramirez BE, Rodriguez-Valdez LM, et al. Quantitative structure-activity relationship of molecules constituent of different essential oils with antimycobacterial activity against Mycobacterium tuberculosis and Mycobacterium bovis. BMC Complement Altern Med. 2015;15:332.

  39. Li WY, Ren JH, Tao NN, Ran LK, Chen X, Zhou HZ, et al. The SIRT1 inhibitor, nicotinamide, inhibits hepatitis B virus replication in vitro and in vivo. Arch Virol. 2016;161(3):621–30.

    Article  PubMed  CAS  Google Scholar 

  40. Sneader W. Drug discovery a history. Cheppenham: Wiley; 2005.

  41. Ntie-Kang F, Zofou D, Babiaka SB, Meudom R, Scharfe M, Lifongo LL, et al. AfroDb: a select highly potent and diverse natural product library from African medicinal plants. PLoS One. 2013;8(10):e78085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Aboubakr HA, Nauertz A, Luong NT, Agrawal S, El-Sohaimy SA, Youssef MM, et al. In vitro antiviral activity of clove and ginger aqueous extracts against feline Calicivirus, a surrogate for human norovirus. J Food Prot. 2016;79(6):1001–12.

    Article  CAS  PubMed  Google Scholar 

  43. Sun WJ, Lv WJ, Li LN, Yin G, Hang X, Xue Y, et al. Eugenol confers resistance to tomato yellow leaf curl virus (TYLCV) by regulating the expression of SlPer1 in tomato plants. New Biotechnol. 2016;33(3):345–54.

    Article  CAS  PubMed  Google Scholar 

  44. Wang C, Fan Y. Eugenol enhances the resistance of tomato against tomato yellow leaf curl virus. J Sci Food Agric. 2014;94(4):677–82.

    Article  CAS  PubMed  Google Scholar 

  45. Dai JP, Zhao XF, Zeng J, Wan QY, Yang JC, Li WZ, et al. Drug screening for autophagy inhibitors based on the dissociation of Beclin1-Bcl2 complex using BiFC technique and mechanism of eugenol on anti-influenza a virus activity. PLoS One. 2013;8(4):e61026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Astani A, Reichling J, Schnitzler P. Screening for antiviral activities of isolated compounds from essential oils. Evid Based Complement Alternat Med. 2011;2011:253643.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Benencia F, Courreges MC. In vitro and in vivo activity of eugenol on human herpesvirus. Phytother Res. 2000;14(7):495–500.

    Article  CAS  PubMed  Google Scholar 

  48. Bourne KZ, Bourne N, Reising SF, Stanberry LR. Plant products as topical microbicide candidates: assessment of in vitro and in vivo activity against herpes simplex virus type 2. Antivir Res. 1999;42(3):219–26.

    Article  CAS  PubMed  Google Scholar 

  49. Turgeon N, Michel K, Ha TL, Robine E, Moineau S, Duchaine C. Resistance of aerosolized bacterial viruses to four germicidal products. PLoS One. 2016;11(12):e0168815.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Pandey SK, Tandon S, Ahmad A, Singh AK, Tripathi AK. Structure-activity relationships of monoterpenes and acetyl derivatives against Aedes aegypti (Diptera: Culicidae) larvae. Pest Manag Sci. 2013;69(11):1235–8.

    CAS  PubMed  Google Scholar 

  51. Marchese A, Barbieri R, Coppo E, Orhan IE, Daglia M, Nabavi SF, et al. Antimicrobial activity of eugenol and essential oils containing eugenol: a mechanistic viewpoint. Crit Rev Microbiol. 2017;43(6):668–89.

    Article  CAS  PubMed  Google Scholar 

  52. Abdullah ML, Hafez MM, Al-Hoshani A, Al-Shabanah O. Anti-metastatic and anti-proliferative activity of eugenol against triple negative and HER2 positive breast cancer cells. BMC Complement Altern Med. 2018;18(1):321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bolton JL, Dunlap TL, Dietz BM. Formation and biological targets of botanical o-quinones. Food Chem Toxicol. 2018;120:700–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Murray CW, Blundell TL. Structural biology in fragment-based drug design. Curr Opin Struct Biol. 2010;20(4):497–507.

    Article  CAS  PubMed  Google Scholar 

  55. Erlanson DA, McDowell RS, O'Brien T. Fragment-based drug discovery. J Med Chem. 2004;47(14):3463–82.

    Article  CAS  PubMed  Google Scholar 

  56. Bembenek SD, Tounge BA, Reynolds CH. Ligand efficiency and fragment-based drug discovery. Drug Discov Today. 2009;14(5–6):278–83.

    Article  CAS  PubMed  Google Scholar 

  57. Showler AT, Harlien JL. Effects of the botanical compound p-Anisaldehyde on horn Fly (Diptera: Muscidae) repellency, mortality, and reproduction. J Med Entomol. 2018;55(1):183–92.

    Article  CAS  PubMed  Google Scholar 

  58. Showler AT, Harlien JL. Botanical compound p-Anisaldehyde repels larval lone star tick (Acari: Ixodidae), and halts reproduction by gravid adults. J Med Entomol. 2018;55(1):200–9.

    Article  CAS  PubMed  Google Scholar 

  59. Zhang QH, Schneidmiller RG, Hoover DR. Essential oils and their compositions as spatial repellents for pestiferous social wasps. Pest Manag Sci. 2013;69(4):542–52.

    Article  CAS  PubMed  Google Scholar 

  60. Swanson JA, Torto B, Kells SA, Mesce KA, Tumlinson JH, Spivak M. Odorants that induce hygienic behavior in honeybees: identification of volatile compounds in chalkbrood-infected honeybee larvae. J Chem Ecol. 2009;35(9):1108–16.

    Article  CAS  PubMed  Google Scholar 

  61. Liu G, Nash PJ, Johnson B, Pietzsch C, Ilagan MX, Bukreyev A, et al. A sensitive in vitro high-throughput screen to identify Pan-filoviral replication inhibitors targeting the VP35-NP Interface. ACS Infect Dis. 2017;(3, 3):190–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Reeves WC. Partners: serendipity in arbovirus research. J Vector Ecol. 2001;26(1):1–6.

    CAS  PubMed  Google Scholar 

  63. Smyth JF. Science and serendipity in cancer research. Eur J Cancer. 2001;37(1):8.

    Article  CAS  PubMed  Google Scholar 

  64. Duffin J. Poisoning the spindle: serendipity and discovery of the anti-tumor properties of the Vinca alkaloids. Pharm Hist. 2002;44(2):64–76.

    PubMed  Google Scholar 

  65. Mao J, Yuan H, Wang Y, Wan B, Pieroni M, Huang Q, et al. From serendipity to rational antituberculosis drug discovery of mefloquine-isoxazole carboxylic acid esters. J Med Chem. 2009;52(22):6966–78.

    Article  CAS  PubMed  Google Scholar 

  66. Howland RH. Serendipity and psychopharmacology. J Psychosoc Nurs Ment Health Serv. 2010;48(10):9–12.

    Article  PubMed  Google Scholar 

  67. Monneret C. Platinum anticancer drugs. From serendipity to rational design. Ann Pharm Fr. 2011;69(6):286–95.

    Article  CAS  PubMed  Google Scholar 

  68. Bolgar B, Arany A, Temesi G, Balogh B, Antal P, Matyus P. Drug repositioning for treatment of movement disorders: from serendipity to rational discovery strategies. Curr Top Med Chem. 2013;13(18):2337–63.

    Article  CAS  PubMed  Google Scholar 

  69. Ekins S, Diaz N, Chung J, Mathews P, McMurtray A. Enabling anyone to translate clinically relevant ideas to therapies. Pharm Res. 2017;34(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  70. Young DW. Considerations related to small-molecule screening collections. In: Bittker JA, Ross NT, editors. High throughput screening methods: evolution and refinement. Cambridge: The Royal Society of Chemistry; 2017. p. 16–36.

    Google Scholar 

  71. Rodrigues T. Harnessing the potential of natural products in drug discovery from a cheminformatics vantage point. Org Biomol Chem. 2017;15(44):9275–82.

    Article  CAS  PubMed  Google Scholar 

  72. Mohamed A, Nguyen CH, Mamitsuka H. Current status and prospects of computational resources for natural product dereplication: a review. Brief Bioinform. 2016;17(2):309–21.

    Article  CAS  PubMed  Google Scholar 

  73. Harvey AL, Edrada-Ebel R, Quinn RJ. The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov. 2015;14(2):111–29.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments and Disclosures

Ms. Kimberley M. Zorn, Dr. Mary A. Lingerfelt and Dr. Alex M. Clark, are kindly acknowledged for their assistance. T.L., and S.E. work for Collaborations Pharmaceuticals, Inc.

Funding

SE kindly acknowledges NIH funding: R21TR001718 from NCATS (PI – Sean Ekins).

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Author notes

  1. Manu Anantpadma & Robert A. Davey

    Present address: National Emerging Infectious Diseases Laboratories, Boston University, 401P, 620 Albany Street, Boston, MA, 02118, USA

Authors and Affiliations

  1. Collaborations Pharmaceuticals, Inc., Main Campus Drive, Lab 3510 Raleigh, North Carolina, 27606, USA

    Thomas Lane & Sean Ekins

  2. Texas Biomedical Research Institute, San Antonio, TX, 78227, USA

    Manu Anantpadma & Robert A. Davey

  3. Departments of Pharmacology & Physiology and Medicine, Center for Emerging and Reemerging Pathogens, Rutgers University – New Jersey Medical School, 185, Avenue Newark, South Orange, NJ, 07103, USA

    Joel S. Freundlich

  4. Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, California, 94025, USA

    Peter B. Madrid

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  1. Thomas Lane
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Correspondence to Sean Ekins.

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Lane, T., Anantpadma, M., Freundlich, J.S. et al. The Natural Product Eugenol Is an Inhibitor of the Ebola Virus In Vitro. Pharm Res 36, 104 (2019). https://doi.org/10.1007/s11095-019-2629-0

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