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The selective effect of Ivermectin on different human coronaviruses; in-vitro study

Shahin et al., Research Square, doi:10.21203/rs.3.rs-4180797/v1

Apr 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.

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

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 112 treatments. c19ivm.org

In Vitro study showing dose-dependent inhibition of wildtype and omicron SARS-CoV-2 with 0.5-5μM ivermectin.

Authors found no significant effect for alphacoronavirus NL63 and a moderate effect for betacoronavirus OC43. In contrast, ivermectin dramatically reduced SARS-CoV-2 wildtype and omicron viral particles by 90% and 95% respectively at 5μM, and showed inhibition starting at 0.5μM for omicron and 1μM for wildtype.

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

32 In Silico studies1-32

24 In Vitro studies33-56

14 In Vivo animal studies43,49,56-67

Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N768, Dengue34,69,70, HIV-170, Simian virus 4071, Zika34,72,73, West Nile73, Yellow Fever74,75, Japanese encephalitis74, Chikungunya75, Semliki Forest virus75, Human papillomavirus54, Epstein-Barr54, BK Polyomavirus76, and Sindbis virus75.

Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins68,70,71,77, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing35, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination38,78, shows dose-dependent inhibition of wildtype and omicron variants33, exhibits dose-dependent inhibition of lung injury58,63, may inhibit SARS-CoV-2 via IMPase inhibition34, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation7, inhibits SARS-CoV-2 3CL^pro51, may inhibit SARS-CoV-2 RdRp activity26, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages57, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation79, may interfere with SARS-CoV-2's immune evasion via ORF8 binding2, may inhibit SARS-CoV-2 by disrupting CD147 interaction80-83, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1956,84, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage6, may minimize SARS-CoV-2 induced cardiac damage37,45, increases Bifidobacteria which play a key role in the immune system85, has immunomodulatory48 and anti-inflammatory67,86 properties, and has an extensive and very positive safety profile87.

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3. de Oliveira Só et al., In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease, Preprints, doi:10.20944/preprints202404.1825.v1.preprints.org, doi.org.

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9. Umar et al., Inhibitory potentials of ivermectin, nafamostat, and camostat on spike protein and some nonstructural proteins of SARS-CoV-2: Virtual screening approach, Jurnal Teknologi Laboratorium, doi:10.29238/teknolabjournal.v11i1.344.teknolabjournal.com, doi.org.

10. Alvarado et al., Interaction of the New Inhibitor Paxlovid (PF-07321332) and Ivermectin With the Monomer of the Main Protease SARS-CoV-2: A Volumetric Study Based on Molecular Dynamics, Elastic Networks, Classical Thermodynamics and SPT, Computational Biology and Chemistry, doi:10.1016/j.compbiolchem.2022.107692.sciencedirect.com, doi.org.

11. Aminpour et al., In Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds, Computation, doi:10.3390/computation10040051.mdpi.com, doi.org.

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13. Francés-Monerris et al., Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection, Physical Chemistry Chemical Physics, doi:10.1039/D1CP02967C.rsc.org, doi.org.

14. González-Paz et al., Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach, Biophysical Chemistry, doi:10.1016/j.bpc.2021.106677.sciencedirect.com, doi.org.

15. González-Paz (B) et al., Structural Deformability Induced in Proteins of Potential Interest Associated with COVID-19 by binding of Homologues present in Ivermectin: Comparative Study Based in Elastic Networks Models, Journal of Molecular Liquids, doi:10.1016/j.molliq.2021.117284.sciencedirect.com, doi.org.

16. Rana et al., A Computational Study of Ivermectin and Doxycycline Combination Drug Against SARS-CoV-2 Infection, Research Square, doi:10.21203/rs.3.rs-755838/v1.researchsquare.com, doi.org.

17. Muthusamy et al., Virtual Screening Reveals Potential Anti-Parasitic Drugs Inhibiting the Receptor Binding Domain of SARS-CoV-2 Spike protein, Journal of Virology & Antiviral Research, www.scitechnol.com/abstract/virtual-screening-reveals-potential-antiparasitic-drugs-inhibiting-the-receptor-binding-domain-of-sarscov2-spike-protein-16398.html.scitechnol.com.

18. Qureshi et al., Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1906750.tandfonline.com, doi.org.

19. Schöning et al., Highly-transmissible Variants of SARS-CoV-2 May Be More Susceptible to Drug Therapy Than Wild Type Strains, Research Square, doi:10.21203/rs.3.rs-379291/v1.researchsquare.com, doi.org.

20. Bello et al., Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1911857.tandfonline.com, doi.org.

21. Udofia et al., In silico studies of selected multi-drug targeting against 3CLpro and nsp12 RNA-dependent RNA-polymerase proteins of SARS-CoV-2 and SARS-CoV, Network Modeling Analysis in Health Informatics and Bioinformatics, doi:10.1007/s13721-021-00299-2.springer.com, doi.org.

22. Choudhury et al., Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach, Future Medicine, doi:10.2217/fvl-2020-0342.futuremedicine.com, doi.org.

23. Kern et al., Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing, Frontiers in Pharmacology, doi:10.3389/fphar.2021.625678.frontiersin.org, doi.org.

24. Saha et al., The Binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2, Structural Chemistry, doi:10.1007/s11224-021-01776-0.researchsquare.com, doi.org.

25. Eweas et al., Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2, Frontiers in Microbiology, doi:10.3389/fmicb.2020.592908.frontiersin.org, doi.org.

26. Parvez (B) et al., Prediction of potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2 using comprehensive drug repurposing and molecular docking approach, International Journal of Biological Macromolecules, doi:10.1016/j.ijbiomac.2020.09.098.sciencedirect.com, doi.org.

27. Francés-Monerris (B) et al., Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent, ChemRxiv, doi:10.26434/chemrxiv.12782258.v1.chemrxiv.org, doi.org.

28. Kalhor et al., Repurposing of the approved small molecule drugs in order to inhibit SARS-CoV-2 S protein and human ACE2 interaction through virtual screening approaches, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2020.1824816.tandfonline.com, doi.org.

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30. Maurya, D., A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients, American Chemical Society (ACS), doi:10.26434/chemrxiv.12630539.v1.chemrxiv.org, doi.org.

31. Lehrer et al., Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2, In Vivo, 34:5, 3023-3026, doi:10.21873/invivo.12134.iiarjournals.org, doi.org.

32. Suravajhala et al., Comparative Docking Studies on Curcumin with COVID-19 Proteins, Preprints, doi:10.20944/preprints202005.0439.v3.preprints.org, doi.org.

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Shahin et al., 18 Apr 2024, preprint, 7 authors.

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

This Paper Ivermectin All

The selective effect of Ivermectin on different human coronaviruses; in-vitro study

Amina Dakeh Shahin, Nofar Atari, Tal Meningher, Oran Erster, Dror Avni, Eli Schwartz, Michal Mandelboim

doi:10.21203/rs.3.rs-4180797/v1

Background: The outbreak of coronavirus disease COVID-19, caused by Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) has become an urgent public health concern worldwide. Although several clinical trials have pointed to new drugs with some anti-COVID-19 activity, we are far from having a safe and effective drug. In this study, we tested the effect of ivermectin on several coronaviruses (serotypes), including variants of SARS-CoV-2. Methods: The effect of ivermectin was tested on cells infected with four different coronaviruses: NL63 (Alphacoronavirus genus.), OC43, SARS-CoV-2, and Omicron (all Betacoronavirus genus). Two hours post-infection, different doses of ivermectin were added to the cell culture. Results: There was no effect of even a high dose of ivermectin on NL63, however, we found a significant effect on OC43 PFU with a 40% inhibition at a dose of 5M. The impact of ivermectin on SARS-CoV-2 and on its Omicron variant was much more pronounced and at a dose of 5M there was inhibition of 90% and 95% respectively. Discussion: Although coronaviruses have been recognized as human pathogens for more than 50 years, no effective treatment strategy exists. Our current study did not demonstrate any effect of ivermectin on Alphacoronavirus but it had a specific impact on the Betacoronavirus genus with a mild impact on OC43 and a decidedly pronounced effect on SARS-CoV-2 including its Omicron variant. Ivermectin should be further studied as a single agent or as part of combined treatment against Coronaviruses.

Author Contributions: A.D.S., N. A., and T.M. performed the experiments. O. E. provided and calibrated the reagent for the RT-qPCR to all coronavirus variants. M. M., D. A., and E. S. conceived and planned the experiments, analyzed and interpreted the results supervised the project, and led the writing of the manuscript. All authors have read and agreed to the published version of the manuscript." Funding: Dakeh Shahin's fellowship was funded by The Meir and Edith Rosenfeld Foundation Institution Institutional Review Board Statement: All the experiments were done in cells in a culture with viruses that were also grown and isolated from cell culture. First isolation of Viruses were from positive nasopharyngeal swab samples. Since the virus was isolated from the swab media that was added to the cells in culture, and in practice no human tissue or material was used, according to the Institutional Review Board committee patient's consent was not required. This was approved by the Institutional Review Board, approval number 7875-20-SM Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Supplementary Files This is a list of supplementary les associated with this preprint. Click to download. supplementary.docx

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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

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