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Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets

Bello et al., Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1911857
Apr 2021  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now with p < 0.00000000001 from 104 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments.
In Silico analysis finding that the in vitro activity of ivermectin may explained by acting as an inhibitor of importin-α, dimeric 3CLpro, and Nsp9.
68 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 H7N766, Dengue32,67,68, HIV-168, Simian virus 4069, Zika32,70,71, West Nile71, Yellow Fever72,73, Japanese encephalitis72, Chikungunya73, Semliki Forest virus73, Human papillomavirus52, Epstein-Barr52, BK Polyomavirus74, and Sindbis virus73.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins66,68,69,75, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing33, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination36,76, shows dose-dependent inhibition of wildtype and omicron variants31, exhibits dose-dependent inhibition of lung injury56,61, may inhibit SARS-CoV-2 via IMPase inhibition32, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation5, inhibits SARS-CoV-2 3CLpro49, may inhibit SARS-CoV-2 RdRp activity24, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages55, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation77, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1954,78, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage4, may minimize SARS-CoV-2 induced cardiac damage35,43, increases Bifidobacteria which play a key role in the immune system79, has immunomodulatory46 and anti-inflammatory65,80 properties, and has an extensive and very positive safety profile81.
Bello et al., 10 Apr 2021, peer-reviewed, 1 author.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets
Martiniano Bello
Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1911857
Ivermectin (IVM) is an FDA-approved drug that has shown antiviral activity against a wide variety of viruses in recent years. IVM inhibits the formation of the importin-a/b1 heterodimeric complex responsible for the translocation and replication of various viral species proteins. Also, IVM hampers SARS-CoV-2 replication in vitro; however, the molecular mechanism through which IVM inhibits SARS-CoV-2 is not well understood. Previous studies have explored the molecular mechanism through which IVM inhibits importin-a and several potential targets associated with COVID-19 by using docking approaches and MD simulations to corroborate the docked complexes. This study explores the energetic and structural properties through which IVM inhibits importin-a and five targets associated with COVID-19 by using docking and MD simulations combined with the molecular mechanics generalized Born surface area (MMGBSA) approach. Energetic and structural analysis showed that the main protease 3CL pro reached the most favorable affinity, followed by importin-a and Nsp9, which shared a similar relationship. Therefore, in vitro activity of IVM can be explained by acting as an inhibitor of importin-a, dimeric 3CL pro , and Nsp9, but mainly over dimeric 3CL pro .
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