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Journal article
VE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry
iScience, v 25(7), 104528
15 Jul 2022
PMID: 35677392
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
• VE607 stabilizes RBD in its “up” conformation•VE607 inhibits SARS-CoV-1 and SARS-CoV-2 variants of concern•VE607 reduces SARS-CoV-2 replication in the lung of infected hACE2-K18 mice
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Details
- Title
- VE607 stabilizes SARS-CoV-2 Spike in the “RBD-up” conformation and inhibits viral entry
- Creators
- Shilei Ding - Centre Hospitalier de l’Université de MontréalIrfan Ullah - Yale UniversityShang Yu Gong - Centre Hospitalier de l’Université de MontréalJonathan R. Grover - Yale UniversityMohammadjavad Mohammadi - Drexel UniversityYaozong Chen - Uniformed Services University of the Health SciencesDani Vézina - Centre Hospitalier de l’Université de MontréalGuillaume Beaudoin-Bussières - Centre Hospitalier de l’Université de MontréalVijay Tailor Verma - Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, CanadaGuillaume Goyette - Centre Hospitalier de l’Université de MontréalFleur Gaudette - Centre Hospitalier de l’Université de MontréalJonathan Richard - Centre Hospitalier de l’Université de MontréalDerek Yang - University of PennsylvaniaAmos B. Smith - University of PennsylvaniaMarzena Pazgier - Uniformed Services University of the Health SciencesMarceline Côté - University of OttawaCameron Abrams - Drexel UniversityPriti Kumar - Yale UniversityWalther Mothes - Yale UniversityPradeep D. Uchil - Yale UniversityAndrés Finzi - Centre Hospitalier de l’Université de MontréalChristian Baron - Université de Montréal
- Publication Details
- iScience, v 25(7), 104528
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000828170300006
- Scopus ID
- 2-s2.0-85132226081
- Other Identifier
- 991019167950104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology