VE607 Stabilizes SARS-CoV-2 Spike In the "RBD-up" Conformation and Inhibits Viral Entry

Ding, S.; Gong, S. Y.; Grover, J.; Mohammadjavad, M.; Chen, Y.; Vezina, D.; Beaudoin-Bussieres, G.; Verma, V. T.; Goyette, G.; Richard, J.; Yang, D.; Smith, A. B.; Pazgier, M.; Cote, M.; Abrams, C.; Mothes, W.; Finzi, A.; Baron, C.

doi:10.1101/2022.02.03.479007

bioRxiv · 10.1101/2022.02.03.479007

VE607 Stabilizes SARS-CoV-2 Spike In the "RBD-up" Conformation and Inhibits Viral Entry

Ding, S.·Gong, S. Y.·Grover, J.·Mohammadjavad, M.·Chen, Y.·Vezina, D.·Beaudoin-Bussieres, G.·Verma, V. T.·Goyette, G.·Richard, J.·Yang, D.·Smith, A. B.·Pazgier, M.·Cote, M.·Abrams, C.·Mothes, W.·Finzi, A.·Baron, C.

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Abstract

SARS-CoV-2 infection of host cells starts by binding of the Spike glycoprotein (S) to the ACE2 receptor. The S-ACE2 interaction is a potential target for therapies against COVID-19 as demonstrated by the development of immunotherapies blocking this interaction. Here, we present the commercially available VE607, comprised of three stereoisomers, that was originally described as an inhibitor of SARS-CoV-1. We show that VE607 specifically inhibits infection of SARS-CoV-1 and SARS-CoV-2 S-expressing pseudoviral particles as well as authentic SARS-CoV-2. VE607 stabilizes the receptor binding domain (RBD) in its "up" conformation. In silico docking and mutational analysis map the VE607 binding site at the RBD-ACE2 interface. The IC50 values are in the low micromolar range for pseudoparticles derived from SARS-CoV-2 Wuhan/D614G as well as from variants of concern (Alpha, Beta, Gamma, Delta and Omicron), suggesting that VE607 has potential for the development of drugs against SARS-CoV-2 infections.

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Ding, S., Gong, S. Y., Grover, J., Mohammadjavad, M., Chen, Y., Vezina, D., Beaudoin-Bussieres, G., Verma, V. T., Goyette, G., Richard, J., Yang, D., Smith, A. B., Pazgier, M., Cote, M., Abrams, C., Mothes, W., Finzi, A., Baron, C.. 2022-02-04. VE607 Stabilizes SARS-CoV-2 Spike In the "RBD-up" Conformation and Inhibits Viral Entry. https://doi.org/10.1101/2022.02.03.479007

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