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

• DOI: 10.1016/j.isci.2022.104528
• Publication Date: 2022-06-03T17:02:15Z
• Authors: Shilei Ding; Irfan Ullah; Shang Yu Gong; Jonathan R. Grover; Mohammadjavad Moh...; Yaozong Chen; Dani Vézina; Guillaume Beaudoi...; 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
• Keywords: spike protein; 2019-20 coronavirus outbreak; Sars virus; Coronavirus

SARS-CoV-2 infection of host cells starts by binding the Spike glycoprotein (S) to ACE2 receptor. The S-ACE2 interaction is a potential target for therapies against COVID-19 as demonstrated development immunotherapies blocking this interaction. VE607 - commercially available compound composed three stereoisomers was described an inhibitor SARS-CoV-1. Here, we show that broadly inhibits pseudoviral particles bearing from major VOCs (D614G, Alpha, Beta, Gamma, Delta, Omicron BA.1, and BA.2) well authentic at low micromolar concentrations. In silico docking, mutational analysis, smFRET revealed binds receptor domain (RBD)-ACE2 interface stabilizes RBD in its "up" conformation. Prophylactic treatment with did not prevent SARS-CoV-2-induced mortality K18-hACE2 mice, but it reduce viral replication lungs 37-fold. Thus, interesting lead drug infection.