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

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 IC 50 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.

• Authors: Shilei Ding, Shang Yu Gong, Jonathan Grover, Mohammadjavad Mohammadi, Yaozong Chen, Dani Vézina, Guillaume Beaudoin-Bussières, Vijay Tailor Verma, Guillaume Goyette, Jonathan Richard, Derek Yang, Amos B Smith, Marzena Pazgier, Marceline Côté, Cameron Abrams, Walther Mothes, Andrés Finzi, Christian Baron
• Journal: bioRxiv : the preprint server for biology (bioRxiv) (Feb 22 2022) United States
• PMID: 35233570 (Publication Type: Preprint)