Identification of inositol monophosphatase as a broad‐spectrum antiviral target of ivermectin
et al., Journal of Medical Virology, doi:10.1002/jmv.29552, Mar 2024
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
|
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.
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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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.
Identification of inositol monophosphatase as a broad‐spectrum antiviral target of ivermectin
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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"abstract": "<jats:title>Abstract</jats:title><jats:p>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.</jats:p>",
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