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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 with p < 0.00000000001 from 105 studies, recognized in 23 countries.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 109 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.
69 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 H7N767, Dengue33,68,69, HIV-169, Simian virus 4070, Zika33,71,72, West Nile72, Yellow Fever73,74, Japanese encephalitis73, Chikungunya74, Semliki Forest virus74, Human papillomavirus53, Epstein-Barr53, BK Polyomavirus75, and Sindbis virus74.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins67,69,70,76, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing34, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination37,77, shows dose-dependent inhibition of wildtype and omicron variants32, exhibits dose-dependent inhibition of lung injury57,62, may inhibit SARS-CoV-2 via IMPase inhibition33, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation6, inhibits SARS-CoV-2 3CLpro50, may inhibit SARS-CoV-2 RdRp activity25, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages56, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation78, may interfere with SARS-CoV-2's immune evasion via ORF8 binding1, may inhibit SARS-CoV-2 by disrupting CD147 interaction79-82, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1955,83, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage5, may minimize SARS-CoV-2 induced cardiac damage36,44, increases Bifidobacteria which play a key role in the immune system84, has immunomodulatory47 and anti-inflammatory66,85 properties, and has an extensive and very positive safety profile86.
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 PaperIvermectinAll
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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'timestamp': 1711018453000}, 'score': 1, 'resource': {'primary': {'URL': 'https://onlinelibrary.wiley.com/doi/10.1002/jmv.29552'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2024, 3]]}, 'references-count': 54, 'journal-issue': {'issue': '3', 'published-print': {'date-parts': [[2024, 3]]}}, 'alternative-id': ['10.1002/jmv.29552'], 'URL': 'http://dx.doi.org/10.1002/jmv.29552', 'relation': {}, 'ISSN': ['0146-6615', '1096-9071'], 'subject': ['Infectious Diseases', 'Virology'], 'container-title-short': 'Journal of Medical Virology', 'published': {'date-parts': [[2024, 3]]}, 'assertion': [ { 'value': '2023-11-22', 'order': 0, 'name': 'received', 'label': 'Received', 'group': {'name': 'publication_history', 'label': 'Publication History'}}, { 'value': '2024-03-10', 'order': 1, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'publication_history', 'label': 'Publication History'}}, { 'value': '2024-03-21', 'order': 2, 'name': 'published', 'label': 'Published', 'group': {'name': 'publication_history', 'label': 'Publication History'}}]}
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