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Microfluidic Diffusion Sizing Applied to the Study of Natural Products and Extracts That Modulate the SARS-CoV-2 Spike RBD/ACE2 Interaction

Fauquet et al., Molecules, doi:10.3390/molecules28248072
Dec 2023  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now known with p < 0.00000000001 from 100 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
In Vitro study showing that ivermectin modulated SARS-CoV-2 spike RBD-ACE2 interaction, suggesting efficacy for COVID-19, at a concentration of 1nM, well below concentrations achieved in practice. Authors use microfluidic diffusional sizing to measure changes in hydrodynamic radius. Promising results were also seen for naringenin and extracts of Rhei radix and Chenopodium quinoa.
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, 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), inhibits SARS-CoV-2 3CLpro Mody, 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, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, 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 Bifidobacterium which plays 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.
Fauquet et al., 13 Dec 2023, peer-reviewed, 5 authors. Contact: (corresponding author),,,,
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Microfluidic Diffusion Sizing Applied to the Study of Natural Products and Extracts That Modulate the SARS-CoV-2 Spike RBD/ACE2 Interaction
Jason Fauquet, Julie Carette, Pierre Duez, Jiuliang Zhang, Amandine Nachtergael
Molecules, doi:10.3390/molecules28248072
The interaction between SARS-CoV-2 spike RBD and ACE2 proteins is a crucial step for host cell infection by the virus. Without it, the entire virion entrance mechanism is compromised. The aim of this study was to evaluate the capacity of various natural product classes, including flavonoids, anthraquinones, saponins, ivermectin, chloroquine, and erythromycin, to modulate this interaction. To accomplish this, we applied a recently developed a microfluidic diffusional sizing (MDS) technique that allows us to probe protein-protein interactions via measurements of the hydrodynamic radius (R h ) and dissociation constant (K D ); the evolution of R h is monitored in the presence of increasing concentrations of the partner protein (ACE2); and the K D is determined through a binding curve experimental design. In a second time, with the protein partners present in equimolar amounts, the R h of the protein complex was measured in the presence of different natural products. Five of the nine natural products/extracts tested were found to modulate the formation of the protein complex. A methanol extract of Chenopodium quinoa Willd bitter seed husks (50 µg/mL; bisdesmoside saponins) and the flavonoid naringenin (1 µM) were particularly effective. This rapid selection of effective modulators will allow us to better understand agents that may prevent SARS-CoV-2 infection.
Author Contributions: Conceptualization, P.D. and A.N.; methodology, J.F.; investigation, J.F. and J.C.; resources, Laboratory of Pharmacognosy and Therapeutic chemistry form UMONS; data curation, J.F.; Visualization, J.Z., writing-original draft preparation, J.C.; writing-review and editing, J.C., A.N., J.F. and P.D. All authors have read and agreed to the published version of the manuscript. Funding: This work was partly supported by Wallonie-Bruxelles International through the project Wallonie-Bruxelles/China (MOST) "Anti-inflammatory herbal medicines and their active components to fight the cytokine storm associated with COVID-19 diseases (TCM-Cyt)". This work was supported by the Fonds pour la Recherche Scientifique FNRS under grant N • CDR J.0058.21 "PlasmLip", which contributed to the acquisition of the fluidity instrument. Veronica Taco is warmly thanked for her analysis of the Chenopodium quinoa husk extract and for giving us access to this sample; Veronica Taco is a scholarship holder from the Académie de Recherche et d'Enseignement Supérieur (ARES, Belgium). This work was also supported by the National Key R&D Program of China, 2021YFE0194000. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. 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..
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