VE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry

Shilei Ding, Irfan Ullah, Shang Yu Gong, Jonathan R. Grover, Mohammadjavad Mohammadi, Yaozong Chen, Dani Vézina, Guillaume Beaudoin-Bussières, Vijay Tailor Verma, Guillaume Goyette, Fleur Gaudette, Jonathan Richard, Derek Yang, Amos B. Smith, Marzena Pazgier, Marceline Côté, Cameron Abrams, Priti Kumar, Walther Mothes, Pradeep D. UchilAndrés Finzi*, Christian Baron*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

SARS-CoV-2 infection of host cells starts by binding 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. VE607 — a commercially available compound composed of three stereoisomers — was described as an inhibitor of SARS-CoV-1. Here, we show that VE607 broadly inhibits pseudoviral particles bearing the Spike from major VOCs (D614G, Alpha, Beta, Gamma, Delta, Omicron – BA.1, and BA.2) as well as authentic SARS-CoV-2 at low micromolar concentrations. In silico docking, mutational analysis, and smFRET revealed that VE607 binds to the receptor binding domain (RBD)-ACE2 interface and stabilizes RBD in its “up” conformation. Prophylactic treatment with VE607 did not prevent SARS-CoV-2-induced mortality in K18-hACE2 mice, but it did reduce viral replication in the lungs by 37-fold. Thus, VE607 is an interesting lead for drug development for the treatment of SARS-CoV-2 infection.

Original languageEnglish
Article number104528
JournaliScience
Volume25
Issue number7
DOIs
StatePublished - 15 Jul 2022
Externally publishedYes

Keywords

  • Drugs
  • Virology

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