Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action

Emanuele Rizzo, Emanuele Rizzo

Abstract

Ivermectin is an antiparasitic drug that has shown also an effective pharmacological activity towards various infective agents, including viruses. This paper proposes an alternative mechanism of action for this drug that makes it capable of having an antiviral action, also against the novel coronavirus, in addition to the processes already reported in literature.

Keywords: Antiviral; COVID-19; Ionophore; Ivermectin; SARS-CoV-2.

Figures

Fig. 1
Fig. 1
Structural formulas of ivermectin compounds
Fig. 2
Fig. 2
Possible interaction mechanism between two ivermectin molecules

References

    1. Abbott BJ, Fukuda DS, Dorman DE, Occolowitz JL, Debono M, Farhner L. Microbial transformation of A23187, a divalent cation ionophore antibiotic. Antimicrob Agents Chemother. 1979;16(6):808–812. doi: 10.1128/AAC.16.6.808.
    1. Ashraf S, Prichard R. Ivermectin exhibits potent anti-mitotic activity. Vet Parasitol. 2016;226:1–4. doi: 10.1016/j.vetpar.2016.06.015.
    1. Ashraf S, Chaudhry U, Raza A, Ghosh D, Zhao X. In vitro activity of ivermectin against Staphylococcus aureus clinical isolates. Antimicrob Resist Infect Control. 2018;7:27. doi: 10.1186/s13756-018-0314-4.
    1. Bakker EP. Ionophore Antibiotics. In: Hahn F.E. (eds) Mechanism of action of antibacterial agents. Antibiotics. 1979;5:1.
    1. Caly L, Wagstaff KM, Jans DA. Nuclear trafficking of proteins from RNA viruses: potential target for anti-virals? Antiviral research. 2012;95:202–206. doi: 10.1016/j.antiviral.2012.06.008.
    1. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;3:104787. doi: 10.1016/j.antiviral.2020.104787.
    1. Cordova A, Deserno M, Gelbart WM, Ben-Shaul A. Osmotic shock and the strength of viral capsids. Biophys J. 2003;85(1):70–74. doi: 10.1016/S0006-3495(03)74455-5.
    1. Crump A. Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations. J Antibiot (Tokyo). 2017;70(5):495–505. doi: 10.1038/ja.2017.11.
    1. Freedman JC (2012) Chapter 4 - Ionophores in planar lipid bilayers. In: Sperelakis N (ed) Cell Physiology Source Book, 4th edn. Academic Press, pp 61–66 ISBN 9780123877383
    1. Geary TG. Ivermectin 20 years on: maturation of a wonder drug. Trends Parasitol. 2005;21(11):530–532. doi: 10.1016/j.pt.2005.08.014.
    1. Gonzalez Canga A, et al. The pharmacokinetics and interactions of ivermectin in humans--a mini-review. AAPS J. 2008;10(1):42–46. doi: 10.1208/s12248-007-9000-9.
    1. Gotz V, et al. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep. 2016;6:23138. doi: 10.1038/srep23138.
    1. Ikehara T, Yamaguchi H, Hosokawa K, Yonezu T, Miyamoto H. Effects of nystatin on intracellular contents and membrane transport of alkali cations, and cell volume in HeLa cells. J Membr Biol. 1986;90(3):231–240. doi: 10.1007/BF01870129.
    1. Intuyod K, Hahnvajanawong C, Pinlaor P, Pinlaor S. Anti-parasitic drug ivermectin exhibits potent anticancer activity against gemcitabine-resistant cholangiocarcinoma in vitro. Anticancer Res. 2019;39(9):4837–4843. doi: 10.21873/anticanres.13669.
    1. Jans DA, Martin AJ, Wagstaff KM. Inhibitors of nuclear transport. Curr Opin Cell Biol. 2019;58:50–60. doi: 10.1016/j.ceb.2019.01.001.
    1. Juarez M, Schcolnik-Cabrera A, Dueñas-Gonzalez A. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res. 2018;8(2):317–331.
    1. Kaushik V, Yakisich JS, Kumar A, Azad N, Iyer AKV. Ionophores: Potential use as anticancer drugs and chemosensitizers. Cancers (Basel) 2018;10(10):pii: E360. doi: 10.3390/cancers10100360.
    1. Klotz U, Ogbuokiri JE, Okonkwo PO. Ivermectin binds avidly to plasma proteins. Eur J Clin Pharmacol. 1990;39(6):607–608. doi: 10.1007/BF00316107.
    1. Krenn BM, Gaudernak E, Holzer B, Lanke K, Van Kuppeveld FJ, Seipelt J. Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections. J Virol. 2009;83(1):58–64. doi: 10.1128/JVI.01543-08.
    1. Lim LE, Vilchèze C, Ng C, Jacobs WR, Jr, Ramón-García S, Thompson CJ. Anthelmintic avermectins kill Mycobacterium tuberculosis, including multidrug-resistant clinical strains. Antimicrob Agents Chemother. 2013;57(2):1040–1046. doi: 10.1128/AAC.01696-12.
    1. Lundberg L, Pinkham C, Baer A, Amaya M, Narayanan A, Wagstaff KM, Jans DA, Kehn-Hall K. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Res. 2013;100(3):662–672. doi: 10.1016/j.antiviral.2013.10.004.
    1. Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, Yan C, Yang Z, Wang X. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res. 2018;159:55–62. doi: 10.1016/j.antiviral.2018.09.010.
    1. Ramos H. Attias de Murciano A, Cohen BE, Bolard J. The polyene antibiotic amphotericin B acts as a Ca2+ ionophore in sterol-containing liposomes. Biochim Biophys Acta. 1989;982(2):303–306. doi: 10.1016/0005-2736(89)90069-2.
    1. Rang PH. Rang and Dale’s pharmacology. In: Dale, Maureen M, Flower RJ, Rod J, editors. 1945-, Henderson, G. (Graeme) (Eighth ed.). [United Kingdom] 2015.
    1. Sandler ZJ, Vu MN, Menachery VD, Mounce BC (2020) Novel ionophores active against La Crosse virus identified through rapid antiviral screening. bioRxiv doi. 10.1101/2020.01.21.914929
    1. Sigrist CJ, Bridge A, Le Mercier P. A potential role for integrins in host cell entry by SARS-CoV-2. Antiviral Res. 2020;177:104759. doi: 10.1016/j.antiviral.2020.104759.
    1. Stillwell W (2016) Chapter 19 - Membrane Transport. In: Stillwell W (ed) An introduction to biological membranes, 2nd edn. Elsevier, pp 423–451 ISBN 9780444637727
    1. Takahashi Y, Matsumoto A, Seino A, Ueno J, Iwai Y, Omura S. Streptomyces avermectinius sp. nov., an avermectin-producing strain. Int J Syst Evol Microbiol. 2002;52(Pt 6):2163–2168.
    1. Tay MY, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor ivermectin. Antiviral Res. 2013;99(3):301–306. doi: 10.1016/j.antiviral.2013.06.002.
    1. te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010;6(11):e1001176. doi: 10.1371/journal.ppat.1001176.
    1. Ventre E, Rozières A, Lenief V, Albert F, Rossio P, Laoubi L, Dombrowicz D, Staels B, Ulmann L, Julia V, Vial E, Jomard A, Hacini-Rachinel F, Nicolas JF, Vocanson M. Topical ivermectin improves allergic skin inflammation. Allergy. 2017;72(8):1212–1221. doi: 10.1111/all.13118.
    1. Wagstaff KM, Rawlinson SM, Hearps AC, Jans DA. An AlphaScreen(R)-based assay for high-throughput screening for specific inhibitors of nuclear import. Journal of biomolecular screening. 2011;16(2):192–200. doi: 10.1177/1087057110390360.
    1. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin alpha/beta mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. The Biochemical journal. 2012;443(3):851–856. doi: 10.1042/BJ20120150.
    1. World Health Organization . World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization; 2019.
    1. Yamasaki M, Tamura N, Nakamura K, Sasaki N, Murakami M, Rajapakshage W, Kumara B, Tamura Y, Lim SY, Ohta H, Takiguchi M. Effects and mechanisms of action of polyene macrolide antibiotic nystatin on Babesia gibsoni in vitro. J Parasitol. 2011;97(6):1190–1192. doi: 10.1645/GE-2799.1.
    1. Yang SNY, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res. 2020;177:104760. doi: 10.1016/j.antiviral.2020.104760.

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