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, Fleur Gaudette, Jonathan Richard, Derek Yang, Amos B. Smith, Marzena Pazgier, Marceline Côté, Cameron Abrams, Priti Kumar, Walther Mothes, Pradeep D. UchilAndrés Finzi^*, Christian Baron^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English
Article number	104528
Journal	iScience
Volume	25
Issue number	7
DOIs	https://doi.org/10.1016/j.isci.2022.104528
State	Published - 15 Jul 2022
Externally published	Yes

Keywords

Drugs
Virology

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Ding, S., Ullah, I., Gong, S. Y., Grover, J. R., Mohammadi, M., Chen, Y., Vézina, D., Beaudoin-Bussières, G., Verma, V. T., Goyette, G., Gaudette, F., Richard, J., Yang, D., Smith, A. B., Pazgier, M., Côté, M., Abrams, C., Kumar, P., Mothes, W., ... Baron, C. (2022). VE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry. iScience, 25(7), Article 104528. https://doi.org/10.1016/j.isci.2022.104528

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

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",

author = "Shilei Ding and Irfan Ullah and Gong, {Shang Yu} and Grover, {Jonathan R.} and Mohammadjavad Mohammadi and Yaozong Chen and Dani V{\'e}zina and Guillaume Beaudoin-Bussi{\`e}res and Verma, {Vijay Tailor} and Guillaume Goyette and Fleur Gaudette and Jonathan Richard and Derek Yang and Smith, {Amos B.} and Marzena Pazgier and Marceline C{\^o}t{\'e} and Cameron Abrams and Priti Kumar and Walther Mothes and Uchil, {Pradeep D.} and Andr{\'e}s Finzi and Christian Baron",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = jul,

day = "15",

doi = "10.1016/j.isci.2022.104528",

language = "English",

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Ding, S, Ullah, I, Gong, SY, Grover, JR, Mohammadi, M, Chen, Y, Vézina, D, Beaudoin-Bussières, G, Verma, VT, Goyette, G, Gaudette, F, Richard, J, Yang, D, Smith, AB, Pazgier, M, Côté, M, Abrams, C, Kumar, P, Mothes, W, Uchil, PD, Finzi, A & Baron, C 2022, 'VE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry', iScience, vol. 25, no. 7, 104528. https://doi.org/10.1016/j.isci.2022.104528

TY - JOUR

T1 - VE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry

AU - Ding, Shilei

AU - Ullah, Irfan

AU - Gong, Shang Yu

AU - Grover, Jonathan R.

AU - Mohammadi, Mohammadjavad

AU - Chen, Yaozong

AU - Vézina, Dani

AU - Beaudoin-Bussières, Guillaume

AU - Verma, Vijay Tailor

AU - Goyette, Guillaume

AU - Gaudette, Fleur

AU - Richard, Jonathan

AU - Yang, Derek

AU - Smith, Amos B.

AU - Pazgier, Marzena

AU - Côté, Marceline

AU - Abrams, Cameron

AU - Kumar, Priti

AU - Mothes, Walther

AU - Uchil, Pradeep D.

AU - Finzi, Andrés

AU - Baron, Christian

PY - 2022/7/15

Y1 - 2022/7/15

N2 - 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.

AB - 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.

KW - Drugs

KW - Virology

UR - http://www.scopus.com/inward/record.url?scp=85132226081&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2022.104528

DO - 10.1016/j.isci.2022.104528

M3 - Article

AN - SCOPUS:85132226081

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 7

M1 - 104528

ER -

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

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