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Basic Characteristics of Mutations
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Mutation Site
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Y505H |
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Mutation Site Sentence
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But when Y505 was replaced with Histidine (H), which is a naturally occurring mutation in Omicron VOCs, the pseudoviral particles harboring Y505H spike became sensitive to VE607 (IC50 = 4.5 muM) (Figure 2D). |
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Mutation Level
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Amino acid level |
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Mutation Type
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Nonsynonymous substitution |
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Gene/Protein/Region
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S |
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Standardized Encoding Gene
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S
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Genotype/Subtype
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Omicron |
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Viral Reference
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-
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Functional Impact and Mechanisms
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Disease
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-
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Immune
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- |
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Target Gene
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-
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Clinical and Epidemiological Correlations
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Clinical Information
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- |
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Treatment
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- |
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Location
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Canada |
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Literature Information
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PMID
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35677392
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Title
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VE607 stabilizes SARS-CoV-2 Spike in the "RBD-up" conformation and inhibits viral entry
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Author
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Ding S,Ullah I,Gong SY,Grover JR,Mohammadi M,Chen Y,Vezina D,Beaudoin-Bussieres G,Verma VT,Goyette G,Gaudette F,Richard J,Yang D,Smith AB 3rd,Pazgier M,Cote M,Abrams C,Kumar P,Mothes W,Uchil PD,Finzi A,Baron C
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Journal
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iScience
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Journal Info
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2022 Jul 15;25(7):104528
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Abstract
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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.
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Sequence Data
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-
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