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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In Silico analysis finding that the in vitro activity of ivermectin may explained by acting as an inhibitor of importin-α, dimeric 3CL^pro, and Nsp9.

57 preclinical studies support the efficacy of ivermectin for COVID-19:

20 In Vitro studies Boschi, Caly, Croci, De Forni, Delandre, Jeffreys, Jitobaom, Jitobaom (B), Li, Liu, Liu (B), Mody, Mountain Valley MD, Munson, Saha (B), Segatori, Surnar, Yesilbag, Zhang, Zheng

13 In Vivo animal studies Abd-Elmawla, Albariqi, Arévalo, Chaccour, de Melo, Errecalde, Ma, Madrid, Mountain Valley MD, Uematsu, Yan, Zhang, Zheng

Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Yang, West Nile Yang, Yellow Fever Mastrangelo, Varghese, Japanese encephalitis Mastrangelo, Chikungunya Varghese, Semliki Forest virus Varghese, Human papillomavirus Li, Epstein-Barr Li, BK Polyomavirus Bennett, and Sindbis virus Varghese.

Ivermectin is an inhibitor of importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), a SARS-CoV-2 3CL^pro inhibitor Mody, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model of severe infection/inflammation that shares key pathological features of severe COVID-19 DiNicolantonio, Zhang, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage Zhao, may minimize SARS-CoV-2 induced cardiac damage Liu, Liu (B), has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.

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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.

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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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