Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients
et al., Viruses, doi:10.3390/v13102084, Oct 2021
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
|
Gene expression analysis of nasopharyngeal swabs of COVID-19 positive and negative patients, and in vitro study supporting the use of ivermectin and atorvastatin for COVID-19, and the efficacy of ivermectin at clinically relevant dosages.
Experiments showed that ivermectin and atorvastatin halted NF-κB activation, impaired importin and Rho GTPases gene expression, and inhibited importin α nuclear accumulation. Authors note that ivermectin and atorvastatin's targetting of importin-mediated nuclear trafficking may also indicate applicability to other infections including dengue fever, zika, and influenza.
Authors show that an ivermectin concentration as low as 0.2μM for 24h produced a similar effect on the inhibition of importin α nuclear to cytoplasmic distribution as that of a 2.5μM for 1h. This suggests that a sustained exposure to lower concentrations could interfere with the host cell machinery that SARS-CoV-2 requires for replication. Experiments also indicate improved results with the combination of ivermectin and atorvastatin.
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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Segatori et al., 15 Oct 2021, peer-reviewed, 11 authors.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients
Viruses, doi:10.3390/v13102084
Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations.
Supplementary Materials: The following are available online at www.mdpi.com/article/10.3390/v13102084/s1; Table S1 : Patient demographics for GSE152075 dataset. Figure S1 : Gene expression in COVID-19 and non-COVID-19 patients categorized by sex. Figure S2 : Gene expression of importins and Rho GTPases in A549 cells and ferrets. Figure S3 : Importin and Rho GTPases gene expression analysis in A549 and HMVEC cells. Author Contributions: Conceptualization, D.F.A., G.G., and E.S.; Methodology, V.I.S., J.G., L.G.C., J.B., R.L., A.T., and P.S.; Software, J.B., R.L., A.T., and P.S.; Validation, J.B., R.L., A.T., and P.S.; Formal analysis, V.I.S., J.G.,J.B., R.L., A.T., and P.S.; Investigation, V.I.S., J.G., J.B., R.L., A.T., and P.S.; Data curation, J.B., R.L., A.T., and P.S.; Writing-original draft preparation, V.I.S., J.G., G.G., and D.F.A.; Writing-review & editing, V.I.S., J.G., J.B., R.L., A.T., P.S., E.S., A.K., G.G., and D.F.A.; Supervision, D.F.A. and G.G.; Project administration, V.I.S. and J.G.; Funding acquisition, G.G., D.F.A., and A.K. All authors have read and agreed to the published version of the manuscript.
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