Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent
et al., ChemRxiv, doi:10.26434/chemrxiv.12782258.v1, Oct 2020
Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.00000000001 from 106 studies, recognized in 24 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
|
In silico study showing that ivermectin is capable of interfering in different key steps of the SARS-CoV-2 replication cycle.
74 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N771, Dengue37,72,73 , HIV-173, Simian virus 4074, Zika37,75,76 , West Nile76, Yellow Fever77,78, Japanese encephalitis77, Chikungunya78, Semliki Forest virus78, Human papillomavirus57, Epstein-Barr57, BK Polyomavirus79, and Sindbis virus78.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins71,73,74,80 , shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing38, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination41,81, shows dose-dependent inhibition of wildtype and omicron variants36, exhibits dose-dependent inhibition of lung injury61,66, may inhibit SARS-CoV-2 via IMPase inhibition37, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation9, inhibits SARS-CoV-2 3CLpro54, may inhibit SARS-CoV-2 RdRp activity28, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages60, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation82, may interfere with SARS-CoV-2's immune evasion via ORF8 binding4, may inhibit SARS-CoV-2 by disrupting CD147 interaction83-86, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1959,87, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage8, may minimize SARS-CoV-2 induced cardiac damage40,48, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation88, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses1, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways35, increases Bifidobacteria which play a key role in the immune system89, has immunomodulatory51 and anti-inflammatory70,90 properties, and has an extensive and very positive safety profile91.
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Francés-Monerris et al., 8 Oct 2020, preprint, 8 authors.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent
The novel SARS-CoV-2 coronavirus is causing a devastating pandemic in 2020, threatening public health in many countries. An unprecedented rapid and global response has been set in motion to identify efficient antiviral agents against SARS-CoV-2, mostly relying on the repurposing of drugs presenting or not previously known antiviral activity. Ivermectin is an approved drug used as antiparasitic in humans and animals with well documented broad-spectrum antiviral properties that emerge from host-directed effects. Recent results reported by Wagstaff and coworkers (Antiviral Research 2020, 178, 104787) show a potent inhibition of SARS-CoV-2 replication in vitro by ivermectin, and clinical trials with human volunteers have already started. However, the mode of action of ivermectin is still largely unknown, especially at the molecular level. Here, we employ advanced molecular dynamics simulations to assess the influence of ivermectin on several key viral protein targets, with the aim to reveal the molecular bases of antiviral mechanisms against SARS-CoV-2. Interestingly, we show that ivermectin could be regarded as a multitarget agent, inhibiting different viral functions. These include blocking the recognition by the SARS-CoV-2 Receptor Binding Domain (RBD) of the Angiotensin-Converting Enzyme 2 (ACE2), the interactions with the two viral proteases 3CL pro and PL pro , and the SARS Unique Domain (SUD) non-structural protein. Hence, the wide spectrum of actions involving i) the interference with cell infection, ii) the inhibition of viral replication, and iii) elusion of the host immune system, could point to an unprecedented synergy between host-and virus-directed effects explaining the high anti-SARS-CoV-2 activity observed for this compound.
Entry for the Table of Contents Molecular dynamics reveal the interaction hotspots between the antiparasitic drug ivermectin and several SARS-CoV-2 structures. These findings suggest a novel dual mechanism of action for this drug, in which both host-directed and virus-directe effects act synergistically to stop SARS-CoV-2 infection.
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DOI record:
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"DOI": "10.26434/chemrxiv.12782258.v1",
"URL": "http://dx.doi.org/10.26434/chemrxiv.12782258.v1",
"abstract": "<jats:p>The novel SARS-CoV-2 coronavirus is causing a devastating pandemic in 2020, threatening public health in many countries. An unprecedented rapid and global response has been set in motion to identify efficient antiviral agents against SARS-CoV-2, mostly relying on the repurposing of drugs presenting or not previously known antiviral activity. Ivermectin is an approved drug used as antiparasitic in humans and animals with well documented broad-spectrum antiviral properties that emerge from host-directed effects. Recent results reported by Wagstaff and coworkers (Antiviral Research <jats:bold>2020</jats:bold>, <jats:italic>178</jats:italic>, 104787) show a potent inhibition of SARS-CoV-2 replication <jats:italic>in vitro </jats:italic>by ivermectin, and clinical trials with human volunteers have already started. However, the mode of action of ivermectin is still largely unknown, especially at the molecular level. Here, we employ advanced molecular dynamics simulations to assess the influence of ivermectin on several key viral protein targets, with the aim to reveal the molecular bases of antiviral mechanisms against SARS-CoV-2. Interestingly, we show that ivermectin could be regarded as a multitarget agent, inhibiting different viral functions. These include blocking the recognition by the SARS-CoV-2 Receptor Binding Domain (RBD) of the Angiotensin-Converting Enzyme 2 (ACE2), the interactions with the two viral proteases 3CL<jats:sup>pro</jats:sup> and PL<jats:sup>pro</jats:sup>, and the SARS Unique Domain (SUD) non-structural protein. Hence, the wide spectrum of actions involving i) the interference with cell infection, ii) the inhibition of viral replication, and iii) elusion of the host immune system, could point to an unprecedented synergy between host- and virus-directed effects explaining the high anti-SARS-CoV-2 activity observed for this compound.</jats:p>",
"accepted": {
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2020,
8,
10
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"author": [
{
"affiliation": [],
"family": "Francés-Monerris",
"given": "Antonio",
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},
{
"ORCID": "http://orcid.org/0000-0002-7577-8242",
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"family": "Garcia-Iriepa",
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"family": "Iriepa",
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{
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"family": "Hognon",
"given": "Cecilia",
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{
"affiliation": [],
"family": "Miclot",
"given": "Tom",
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{
"ORCID": "http://orcid.org/0000-0001-8773-2359",
"affiliation": [],
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"family": "Barone",
"given": "Giampaolo",
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{
"ORCID": "http://orcid.org/0000-0001-9464-1463",
"affiliation": [
{
"name": "Université de Lorraine - Nancy & CNRS"
}
],
"authenticated-orcid": false,
"family": "Monari",
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{
"ORCID": "http://orcid.org/0000-0001-7158-7994",
"affiliation": [],
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"family": "Marazzi",
"given": "Marco",
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2020,
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"start": {
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"subtype": "preprint",
"title": "Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent",
"type": "posted-content"
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