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

3 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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10.1016/j.isci.2022.104528

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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), [104528]. https://doi.org/10.1016/j.isci.2022.104528

@article{65ca9c3ec6d0455c9746ddf0d81f206c,

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 = "Funding Information: The authors thank the CRCHUM BSL3 and Flow Cytometry Platforms for technical assistance. The authors thank Hughes Charest and the LSPQ for the authentic SARS-CoV-2 virus. This work was supported by “Minist{\`e}re de l{\textquoteright}{\'E}conomie et de l{\textquoteright}Innovation du Qu{\'e}bec , Programme de soutien aux organismes de recherche et d{\textquoteright}innovation ”, by the Fondation du CHUM , by a Canadian Institutes of Health Research (CIHR) foundation grant # 352417 and by an Exceptional Fund COVID-19 from the Canada Foundation for Innovation (CFI) # 41027 to A.F, and by R01 AI163395 from NIH NIAID to W.M. Work on the presented variants was also supported by the Sentinelle COVID Quebec network led by the LSPQ in collaboration with Fonds de Recherche du Qu{\'e}bec Sant{\'e} (FRQS) to A.F. The work was also supported by the Universit{\'e} de Montr{\'e}al Faculty of Medicine fund “ Combattre la COVID-19: de la prevention au controle ” to C.B. and A.F.; A.F. is the recipient of a Canada Research Chair on Retroviral Entry # RCHS0235 950-232424 . G.B.B. is the recipient of a Fonds de Recherche Qu{\'e}bec— Sant{\'e} (FRQS) PhD fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The graphical abstract was created with BioRender.com .The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Uniformed Services University, the US Army, the Department of Defense, or the US Government. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = jul,

day = "15",

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

language = "English",

volume = "25",

journal = "iScience",

issn = "2589-0042",

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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

N1 - Funding Information: The authors thank the CRCHUM BSL3 and Flow Cytometry Platforms for technical assistance. The authors thank Hughes Charest and the LSPQ for the authentic SARS-CoV-2 virus. This work was supported by “Ministère de l’Économie et de l’Innovation du Québec , Programme de soutien aux organismes de recherche et d’innovation ”, by the Fondation du CHUM , by a Canadian Institutes of Health Research (CIHR) foundation grant # 352417 and by an Exceptional Fund COVID-19 from the Canada Foundation for Innovation (CFI) # 41027 to A.F, and by R01 AI163395 from NIH NIAID to W.M. Work on the presented variants was also supported by the Sentinelle COVID Quebec network led by the LSPQ in collaboration with Fonds de Recherche du Québec Santé (FRQS) to A.F. The work was also supported by the Université de Montréal Faculty of Medicine fund “ Combattre la COVID-19: de la prevention au controle ” to C.B. and A.F.; A.F. is the recipient of a Canada Research Chair on Retroviral Entry # RCHS0235 950-232424 . G.B.B. is the recipient of a Fonds de Recherche Québec— Santé (FRQS) PhD fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The graphical abstract was created with BioRender.com .The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Uniformed Services University, the US Army, the Department of Defense, or the US Government. Publisher Copyright: © 2022 The Author(s)

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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Keywords

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