iScience
Volume 25, Issue 7, 15 July 2022, 104528
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Article
VE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry

https://doi.org/10.1016/j.isci.2022.104528Get rights and content
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Highlights

  • VE607 stabilizes RBD in its “up” conformation

  • VE607 inhibits SARS-CoV-1 and SARS-CoV-2 variants of concern

  • VE607 reduces SARS-CoV-2 replication in the lung of infected hACE2-K18 mice

Summary

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.

Subject areas

Drugs
Virology

Data and code availability

  • All data reported in this paper will be shared by the lead contact ([email protected]) upon request.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact ([email protected]) upon request.

Cited by (0)

11

These authors contributed equally

12

Lead contact