The mechanisms of action of ivermectin against SARS-CoV-2—an extensive review
Asiya Kamber Zaidi, Puya Dehgani-Mobaraki
The Journal of Antibiotics, doi:10.1038/s41429-021-00491-6
Considering the urgency of the ongoing COVID-19 pandemic, detection of new mutant strains and potential re-emergence of novel coronaviruses, repurposing of drugs such as ivermectin could be worthy of attention. This review article aims to discuss the probable mechanisms of action of ivermectin against SARS-CoV-2 by summarizing the available literature over the years. A schematic of the key cellular and biomolecular interactions between ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications has been proposed.
Conflict of interest The authors declare no competing interests. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
Ackermann, Verleden, Kuehnel, Haverich, Welte et al., Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2015432Arshad, Pertinez, Box, Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics, Clin Pharmacol Ther,
doi:10.1002/cpt.1909Bennett, Zhao, Bosard, Imperiale, Role of a nuclear localization signal on the minor capsid proteins VP2 and VP3 in BKPyV nuclear entry, Virology,
doi:10.1016/j.virol.2014.10.013.Bharadwaj, Kasembeli, Robinson, Tweardy, Targeting janus kinases and signal transducer and activator of transcription 3 to treat inflammation, fibrosis, and cancer: rationale, progress, and caution, Pharm Rev
Chandler, Serious neurological adverse events after ivermectin-do they occur beyond the indication of onchocerciasis?, Am J Trop Med Hyg,
doi:10.4269/ajtmh.17-0042.Chen, Zheng, Liu, Yan, Xu et al., Plasma CRP level is positively associated with the severity of COVID-19, Ann Clin Microbiol Antimicrob
Choudhury, Das, Patra, Bhattacharya, Ghosh et al., Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach, Future Virol,
doi:10.2217/fvl-2020-0342Ci, Li, Yu, Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway, Fundam Clin Pharm
Crump, Ōmura, Ivermectin, 'wonder drug' from Japan: the human use perspective, Proc Jpn Acad Ser B Phys Biol Sci,
doi:10.2183/pjab.87.13.Diao, Wang, Tan, Chen, Liu et al., Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19), Front Immunol
Dominguez-Gomez, Chavez-Blanco, Medina-Franco, Saldivar-Gonzalez, Flores-Torrontegui et al., Ivermectin as an inhibitor of cancer stem-like cells, Mol Med Rep,
doi:10.3892/mmr.2017.8231.Dou, Chen, Wang, Yuan, Lei et al., Ivermectin induces cytostatic autophagy by blocking the PAK1/Akt axis in breast cancer, Cancer Res
Dueñas-González, Juárez-Rodríguez, Ivermectin: potential repurposing of a versatile antiparasitic as a novel anticancer,
doi:10.5772/intechopen.99813Edwards, Dingsdale, Helsby, Orme, Breckenridge, The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution, Eur J Clin Pharm
Eweas, Alhossary, As, Molecular docking reveals ivermectin and remdesivir as potential repurposed drugs against SARS-CoV-2, Front Microbiol,
doi:10.3389/fmicb.2020.592908Freedman, Chapter 4-Ionophores in planar lipid bilayers
Frieman, Yount, Heise, Kopecky-Bromberg, Palese et al., Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/golgi membrane, J Virol
Fulcher, Jans, Regulation of nucleocytoplasmic trafficking of viral proteins; an integral role in pathogenesis?, Biochem Biophys Acta Mol Cell Res
Hadjadj, Yatim, Barnabei, Corneau, Boussier et al., Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients, Science
Heidary, Gharebaghi, Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen, J Antibiot,
doi:10.1038/s41429-020-0336-z.Jiang, Wang, Sun, Wu, Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway, J Exp Clin Cancer Res,
doi:10.1186/s13046-019-1251-7Juarez, Schcolnik-Cabrera, Dueñas-Gonzalez, The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug, Am J Cancer Res
Kim, Choi, Kim, Lee, The PAK1-Stat3 signaling pathway activates IL-6 gene transcription and human breast cancer stem cell formation, Cancers
Kircik, Rosso, Layton, Schauber, Over 25 years of clinical experience with ivermectin: an overview of safety for an increasing number of indications, J Drugs Dermatol
Klotz, Ogbuokiri, Okonkwo, Ivermectin binds avidly to plasma proteins, Eur J Clin Pharmacol,
doi:10.1007/BF00316107.Konno, Kimura, Uriu, Fukushi, Irie et al., SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant, Cell Rep,
doi:10.1016/j.celrep.2020.108185Kumar, Jeyaraman, Jain, Anudeep, A wonder drug in the arsenal against COVID-19: medication evidence from ivermectin, J Adv Med Med Res
Layhadi, Turner, Crossman, Fountain, ATP evokes Ca 2+ responses and CXCL5 secretion via P2X4 receptor activation in human monocyte-derived macrophages, J Immunol,
doi:10.4049/jimmunol.1700965.Lehrer, Rheinstein, Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2, Vivo,
doi:10.21873/invivo.12134Ma, Wu, Shaw, Gao, Wang et al., Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex, Proc Natl Acad Sci
Melo, Lazarini, Larrous, Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin, EMBO Mol Med,
doi:10.15252/emmm.202114122.Mielech, Kilianski, Baez-Santos, Mesecar, Baker, MERS-CoV papain-like protease has deISGylating and deubiquitinating activities, Virology
Mody, Ho, Wills, Mawri, Lawson et al., Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents, Commun Biol,
doi:10.1038/s42003-020-01577-xNagai, Satomi, Abiru, Miyamoto, Nagasawa et al., Antihypertrophic effects of small molecules that maintain mitochondrial ATP levels under hypoxia, EBio-Medicine,
doi:10.1016/j.ebiom.2017.09.022Novac, Challenges and opportunities of drug repositioning, Trends Pharm Sci
Park, Iwasaki, Type I. and type III interferons-induction, signaling, evasion, and application to combat COVID-19, Cell Host Microbe
Priel, Silberberg, Mechanism of ivermectin facilitation of human P2X4 receptor channels, J Gen Physiol,
doi:10.1085/jgp.200308986Principletrial, Join the PRINCIPLE
Raza, Shahin, Zhai, Ivermectin inhibits bovine herpesvirus 1 DNA polymerase nuclear import and interferes with viral replication, Microorganisms,
doi:10.3390/microorganisms8030409Scheim, Ivermectin for COVID-19 Treatment: Clinical Response at Quasi-Threshold Doses Via Hypothesized Alleviation of CD147-Mediated Vascular Occlusion
Sekimoto, Imamoto, Nakajima, Hirano, Yoneda, Extracellular signal-dependent nuclear import of Stat1 is mediated by nuclear pore-targeting complex formation with NPI-1, but not Rch1, EMBO J
Seth, Mas, Conod, Mueller, Siems et al., LongLasting WNT-TCF response blocking and epigenetic modifying activities of withanolide f in human cancer cells, PLoS ONE
Stokes, Layhadi, Bibic, Dhuna, Fountain, P2X4 receptor function in the nervous system and current breakthroughs in pharmacology, Front Pharm,
doi:10.3389/fphar.2017.00291.Swargiary, Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against SARS-CoV2: evidence from in silico studies,
doi:10.21203/rs.3.rs-73308/v1Verrest, Dorlo, Lack of clinical pharmacokinetic studies to optimize the treatment of neglected tropical diseases: a systematic review, Clin Pharmacokinet
Wagstaff, Rawlinson, Hearps, Jans, An AlphaScreen(R)-based assay for high-throughput screening for specific inhibitors of nuclear import, J Biomol Screen,
doi:10.1177/1087057110390360.Wu, Fossali, Hypoalbuminemia in COVID-19: assessing the hypothesis for underlying pulmonary capillary leakage, J Intern Med,
doi:10.1111/joim.13208Wu, Peng, Huang, Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China, Cell Host Microbe,
doi:10.1016/j.chom.2020.02.001Yagisawa, Foster, Hanaki, Ōmura, Global trends in clinical studies of ivermectin in COVID-19, Jpn J Antibiotics
Yan, Ci, Chen, Anti-inflammatory effects of ivermectin in mouse model of allergic asthma, Inflamm Res
Yang, Atkinson, Wang, Lee, Bogoyevitch et al., The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antivir Res
Yang, Chu, Hou, Chai, Shuai et al., Attenuated interferon and pro-inflammatory response in SARSCoV-2-infected human dendritic cells is associated with viral antagonism of STAT1 phosphorylation, J Infect Dis,
doi:10.1093/infdis/jiaa356Zaidi, Dawoodi, Pirro, Monti, Mobaraki, Key role of annexin A2 and plasmin in COVID-19 pathophysiology, clinical presentation and outcomes-a review, Ital J Prev, Diagn Ther Med,
doi:10.30459/2020-24Zhang, Song, Ci, Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice, Inflamm Res,
doi:10.1007/s00011-008-8007-8Zheng, Peng, Xu, Zhao, Liu et al., Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis, J Infect,
doi:10.1016/j.jinf.2020.04.021Zheng, Yu, Feng, Lou, Zou, Viral load dynamics and disease severity in patients infected with SARSCoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study, BMJ
