VE607 stabilizes SARS-CoV-2 Spike in the "RBD-up" conformation and inhibits viral entry.
iScience
; 25(7): 104528, 2022 Jul 15.
Article
in English
| MEDLINE | ID: covidwho-1945337
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Topics:
Variants
Language:
English
Journal:
IScience
Year:
2022
Document Type:
Article
Affiliation country:
J.isci.2022.104528
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