biostudies-literatureUnknown25(7)Ding SSARS-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. <i>In silico</i> 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.iScience104528https://www.ebi.ac.uk/biostudies/studies/S-EPMC9164512biostudies-literatureVE607 stabilizes SARS-CoV-2 Spike in the "RBD-up" conformation and inhibits viral entry.PMC9164512Pazgier MGong SYVerma VTUchil PDYang DKumar PCote MBaron CVezina DBeaudoin-Bussieres GMothes WFinzi ADing SRichard JMohammadi MSmith ABGaudette FAbrams CUllah IGoyette GGrover JRChen YfalseVE607 stabilizes SARS-CoV-2 Spike in the "RBD-up" conformation and inhibits viral entry.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. <i>In silico</i> 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.2022-01-01T00:00:00Z2022 Jul2024-11-09T12:44:45.288Z2024-11-09T12:44:45.288ZS-EPMC91645123567739210.1016/j.isci.2022.104528