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 3rd; 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

iScience. 2022 Jul 15;25(7):104528. doi: 10.1016/j.isci.2022.104528. Epub 2022 Jun 3.

Authors

Shilei Ding¹, Irfan Ullah², Shang Yu Gong^{1

3}, Jonathan R Grover⁴, Mohammadjavad Mohammadi⁵, Yaozong Chen⁶, Dani Vézina^{1

7}, Guillaume Beaudoin-Bussières^{1

7}, Vijay Tailor Verma⁸, Guillaume Goyette¹, Fleur Gaudette¹, Jonathan Richard^{1

7}, Derek Yang⁹, Amos B Smith 3rd⁹, Marzena Pazgier⁶, Marceline Côté¹⁰, Cameron Abrams⁵, Priti Kumar², Walther Mothes⁴, Pradeep D Uchil⁴, Andrés Finzi^{1

3

7}, Christian Baron⁸

Affiliations

¹ Centre de recherche du CHUM, Montréal, QC, Canada.
² Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.
³ Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
⁴ Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA.
⁵ Department of Chemical and Biological Engineering, Drexel University, Philadelphia, PA 19104, USA.
⁶ Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA.
⁷ Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC, Canada.
⁸ Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada.
⁹ Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Biochemistry, Microbiology and Immunology, Center for Infection, Immunity, and Inflammation, University of Ottawa, Ottawa, ON K1H 8M5, Canada.

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.

Keywords: Drugs; Virology.

Grants and funding

R01 AI163395/AI/NIAID NIH HHS/United States