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In Vitro Analysis of SARS-CoV-2 Spike Protein and Ivermectin Interaction

García-Aguilar et al., International Journal of Molecular Sciences, doi:10.3390/ijms242216392
Nov 2023  
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Ivermectin for COVID-19
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In Vitro analysis showing a definitive interaction between ivermectin and the spike (S) protein of SARS-CoV-2, suggesting therapeutic potential for COVID-19. Using equilibrium dialysis and UV–Vis techniques, the study determined the affinity and dissociation constants between ivermectin and the S protein, finding an association constant (Ka) of 1.22 µM−1 and a dissociation constant (Kd) of 0.81 µM. Additionally, the Drug Affinity Responsive Target Stability (DARTS) method was employed, confirming the interaction in ratios of 1:50 pmol and 1:100 pmol (S: ivermectin).
Figure 2 shows the binding affinity curve between ivermectin and the spike protein S1/S2 fragment using equilibrium dialysis, showing the Ka and Kd values that indicate direct binding between ivermectin and spike. Figure 3 illustrates the Drug Affinity Responsive Target Stability (DARTS) gel showing protection of the spike protein from degradation when bound to ivermectin. This provides further evidence of direct binding between ivermectin and spike. Figure 4 compares the densitometry analysis of the DARTS gels, showing increased protection of spike protein at higher ivermectin doses. This supports the dose-dependent binding of ivermectin to spike.
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 3CLpro 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.
García-Aguilar et al., 16 Nov 2023, peer-reviewed, 7 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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In Vitro Analysis of SARS-CoV-2 Spike Protein and Ivermectin Interaction
Alejandra García-Aguilar, Rebec Campi-Caballer, Giovani Visoso-Carvajal, José Rubén García-Sánchez, José Correa-Basurto, Jazmín García-Machorro, Judith Espinosa-Raya
The spike (S) protein of SARS-CoV-2 is a molecular target of great interest for developing drug therapies against COVID-19 because S is responsible for the interaction of the virus with the host cell receptor. Currently, there is no outpatient safety treatment for COVID-19 disease. Furthermore, we consider it of worthy importance to evaluate experimentally the possible interaction of drugs (approved by the Food and Drug Administration) and the S, considering some previously in silico and clinical use. Then, the objective of this study was to demonstrate the in vitro interaction of ivermectin with S. The equilibrium dialysis technique with UV-Vis was performed to obtain the affinity and dissociation constants. In addition, the Drug Affinity Responsive Target Stability (DARTS) technique was used to demonstrate the in vitro interaction of S with ivermectin. The results indicate the interaction between ivermectin and the S with an association and dissociation constant of Ka = 1.22 µM -1 and Kd = 0.81 µM, respectively. The interaction was demonstrated in ratios of 1:50 pmol and 1:100 pmol (S: ivermectin) by the DARTS technique. The results obtained with these two different techniques demonstrate an interaction between S and ivermectin previously explored in silico, suggesting its clinical uses to stop the viral spread among susceptible human hosts.
Supplementary Materials: The supporting information can be downloaded at: https://www.mdpi. com/article/10.3390/ijms242216392/s1. Conflicts of Interest: The authors declare no conflict of interest.
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