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. Uchil; Andrés Finzi; Christian Baron

doi:10.1016/j.isci.2022.104528

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, …

iScience, v 25(7), 104528

15 Jul 2022

: https://doi.org/10.1016/j.isci.2022.104528

: 35677392

(1)

url

https://doi.org/10.1016/j.isci.2022.104528

Published, Version of Record (VoR)

Drugs

Virology

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. • 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

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

: VE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry
: Shilei Ding - Centre Hospitalier de l’Université de Montréal
Irfan Ullah - Yale University
Shang Yu Gong - Centre Hospitalier de l’Université de Montréal
Jonathan R. Grover - Yale University
Mohammadjavad Mohammadi - Drexel University
Yaozong Chen - Uniformed Services University of the Health Sciences
Dani Vézina - Centre Hospitalier de l’Université de Montréal
Guillaume Beaudoin-Bussières - Centre Hospitalier de l’Université de Montréal
Vijay Tailor Verma - Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada
Guillaume Goyette - Centre Hospitalier de l’Université de Montréal
Fleur Gaudette - Centre Hospitalier de l’Université de Montréal
Jonathan Richard - Centre Hospitalier de l’Université de Montréal
Derek Yang - University of Pennsylvania
Amos B. Smith - University of Pennsylvania
Marzena Pazgier - Uniformed Services University of the Health Sciences
Marceline Côté - University of Ottawa
Cameron Abrams - Drexel University
Priti Kumar - Yale University
Walther Mothes - Yale University
Pradeep D. Uchil - Yale University
Andrés Finzi - Centre Hospitalier de l’Université de Montréal
Christian Baron - Université de Montréal
: iScience, v 25(7), 104528
: Elsevier
: Journal article
: English
: Chemical and Biological Engineering
: WOS:000828170300006
: 2-s2.0-85132226081
: 991019167950104721

research.portal.fulldisplay.sdgs.intro

research.portal.fulldisplay.sdgs.source

research.portal.fulldisplay.incitesHighlights.intro

esploro.research.conf.research.portal.label.prefix.inciteCollaboration: research.portal.fulldisplay.incitesHighlights.institutionCollaboration; research.portal.fulldisplay.incitesHighlights.internationalCollaboration
esploro.research.conf.research.portal.label.prefix.inciteWOSResearchAreas: Biochemistry & Molecular Biology