Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents
et al., Communications Biology, doi:10.1038/s42003-020-01577-x, Jan 2021
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
|
Computational molecular modeling screening and in vitro analysis for inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme, showing that ivermectin blocked more than 85% of 3CLpro activity of SARS-CoV-2. Antiviral activity of ivermectin mediated through the blocking of α/β1 importin has been previously established, this analysis suggests an additional antiviral mechanism of ivermectin for SARS-CoV-2 via inhibitory effects on 3CLpro.
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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Mody et al., 20 Jan 2021, peer-reviewed, 9 authors.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents
Communications Biology, doi:10.1038/s42003-020-01577-x
Emerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.
Supplementary Data 1 provides the data set for Figs. 2-5 , and Supplementary Figure 2 and 3 . Supplementary Data 2 and 3 provides data set for 3CLpro-OTDs docking study and Supplementary Data 4 for PIs and VNIs (S score for Table 1 and structural analysis for Fig. 6 ). Supplementary Data 5 provides data set for MD simulation study of 3CLPro homodimer with ivermectin, Supplementary Data 6 for 3CLPro monomer with ivermectin and Supplementary Data 7 for 3CLPro monomer with micafungin (Fig. 7 ). Supplementary Data 5-7 provides data set for Supplementary Fig. 3 (S score comparison from MD simulation study). Any remaining information can be obtained from the corresponding author upon reasonable request.
Author contributions V.M. and S.T. designed, performed and wrote the manuscript, S.R. performed the experiment and proofread the manuscript. M.E. performed MD simulation studies. G.M.F. helped with molecular docking studies. J.H., S.W., A.M., and L.L. collected the data on drugs. All authors reviewed the manuscript.
Competing interests The authors declare no competing interests.
Additional information Supplementary information is available for this paper at https://doi.org/10.1038/s42003-020-01577-x. Correspondence and requests for materials should be addressed to S.T. Reprints and permission information is available at http://www.nature.com/reprints Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and..
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Zumla, Chan, Azhar, Hui, Yuen, Coronavirusesdrug discovery and therapeutic options, Nat. Rev. Drug Discov
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