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Identification of inositol monophosphatase as a broad‐spectrum antiviral target of ivermectin

Jitobaom et al., Journal of Medical Virology, doi:10.1002/jmv.29552

Mar 2024

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Ivermectin for COVID-19

4th treatment shown to reduce risk in August 2020

^*, now known with p < 0.00000000001 from 102 studies, recognized in 22 countries.

Lower risk for mortality, ventilation, ICU admission, hospitalization, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine complementary and synergistic treatments. ^* >10% efficacy in meta analysis with ≥3 clinical studies.

4,100+ studies for 60+ treatments. c19ivm.org

In vitro study showing that ivermectin inhibits dengue, Zika, and SARS-CoV-2 by targeting the host protein inositol monophosphatase (IMPase). Authors used thermal proteomic profiling to identify IMPase as a target of ivermectin in human cells. Ivermectin inhibited IMPase activity, reduced cellular myo-inositol and phosphatidylinositol-4-phosphate levels, and this inhibition could be partially reversed with inositol. The results suggest that inhibition of IMPase leading to depletion of cellular myo-inositol and phosphatidylinositol-4-phosphate may be an important antiviral mechanism of ivermectin against various RNA viruses that depend on these molecules for replication organelle formation. Results focus on dengue and Zika, perhaps due to issues related to publishing positive results for SARS-CoV-2, however Figure 6 shows 2µm ivermectin inhibiting SARS-CoV-2.

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

14 In Vivo animal studies Abd-Elmawla, Albariqi, Arévalo, Chaccour, de Melo, Errecalde, Gao, 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 Jitobaom, Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Jitobaom, 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 inhibits importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing Fauquet, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, Scheim, shows dose-dependent inhibition of wildtype and omicron variants Shahin, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 via IMPase inhibition Jitobaom, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, inhibits SARS-CoV-2 3CL^pro Mody, may inhibit SARS-CoV-2 RdRp activity Parvez (B), may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages Gao, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation Liu (C), shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing 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), increases Bifidobacteria which play a key role in the immune system Hazan, has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.

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Jitobaom et al., 21 Mar 2024, peer-reviewed, 9 authors. Contact: prasert.aue@mahidol.ac.th.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Ivermectin All

Identification of inositol monophosphatase as a broad‐spectrum antiviral target of ivermectin

Kunlakanya Jitobaom, Paleerath Peerapen, Usa Boonyuen, Ittipat Meewan, Chompunuch Boonarkart, Thanyaporn Sirihongthong, Songkran Thongon, Visith Thongboonkerd, Prasert Auewarakul

Journal of Medical Virology, doi:10.1002/jmv.29552

Ivermectin has broad-spectrum antiviral activities. Despite the failure in clinical application of COVID-19, it can serve as a lead compound for the development of more effective broad-spectrum antivirals, for which a better understanding of its antiviral mechanisms is essential. We thus searched for potential novel targets of ivermectin in host cells by label-free thermal proteomic profiling using Huh-7 cells. Inositol monophosphatase (IMPase) was found among the proteins with shifted thermal stability by ivermectin. Ivermectin could inhibit IMPase activity and reduce cellular myo-inositol and phosphatidylinositol-4-phosphate levels. On the other hand, inositol could impair the antiviral activity of ivermectin and lithium, an IMPase inhibitor with known antiviral activity. As phosphatidylinositol phosphate is crucial for the replication of many RNA viruses, inhibition of cellular myo-inositol biosynthesis may be an important antiviral mechanism of ivermectin. Hence, inhibition of IMPase could serve as a potential target for broad-spectrum antiviral development.

AUTHOR CONTRIBUTIONS Kunlakanya CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. SUPPORTING INFORMATION Additional supporting information can be found online in the Supporting Information section at the end of this article. How to cite this article: Jitobaom K, Peerapen P, Boonyuen

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