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Spike protein receptor-binding domains from SARS-CoV-2 variants of interest bind human ACE2 more tightly than the prototype spike protein.

ABSTRACT: Several SARS-CoV-2 variants of interest (VOI) have emerged since this virus was first identified as the etiologic agent responsible for COVID-19. Some of these variants have demonstrated differences in both virulence and transmissibility, as well as in evasion of immune responses in hosts vaccinated against the original strain of SARS-CoV-2. There remains a lack of definitive evidence that identifies the genetic elements that are responsible for the differences in transmissibility among these variants. One factor affecting transmissibility is the initial binding of the surface spike protein (SP) of SARS-CoV-2 to human angiotensin converting enzyme-2 (hACE2), the widely accepted receptor for SP. This step in the viral replication process is mediated by the receptor binding domain (RBD) of SP that is located on the surface of the virus. This current study was conducted with the aim of assessing potential differences in binding affinity between recombinant hACE2 and the RBDs of emergent SARS-CoV-2 WHO VOIs. Mutations that affect the binding affinity of SP play a dominant initial role in the infectivity of the virus.

SUBMITTER: Charles J

PROVIDER: S-EPMC9721372 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Spike protein receptor-binding domains from SARS-CoV-2 variants of interest bind human ACE2 more tightly than the prototype spike protein.

Charles Jermilia J McCann Nathan N Ploplis Victoria A VA Castellino Francis J FJ

Biochemical and biophysical research communications 20221205

Several SARS-CoV-2 variants of interest (VOI) have emerged since this virus was first identified as the etiologic agent responsible for COVID-19. Some of these variants have demonstrated differences in both virulence and transmissibility, as well as in evasion of immune responses in hosts vaccinated against the original strain of SARS-CoV-2. There remains a lack of definitive evidence that identifies the genetic elements that are responsible for the differences in transmissibility among these va ...[more]

PMID: 36525925

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Here, we used a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to identify those that bind to human ACE2 or the SARS-CoV-2 spike protein receptor binding domain (RBD). Molecular modeling screening interrogated 57,641 compounds and focused on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein and vice versa. SPR screening used immobilized human ACE2 and SARS-CoV-2 Spike protein to evaluate the binding of these proteins to a library of 3,141 compounds. These combined screens identified compounds from these libraries that bind at KD (equilibrium dissociation constant) <3 μM affinity to their respective targets, 17 for ACE2 and 6 for SARS-CoV-2 RBD. Twelve ACE2 binders and six of the RBD binders compete with the RBD-ACE2 interaction in an SPR-based competition assay. These compounds included registered drugs and dyes used in biomedical applications. A Vero-E6 cell-based SARS-CoV-2 infection assay was used to evaluate infection blockade by candidate entry inhibitors. Three compounds demonstrated dose-dependent antiviral in vitro potency-Evans blue, sodium lifitegrast, and lumacaftor. This study has identified potential drugs for repurposing as SARS-CoV-2 entry inhibitors or as chemical scaffolds for drug development.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases. Using an in silico screen of 57,641 compounds and a biophysical screen of 3,141 compounds, we identified 22 compounds that bound to either the angiotensin converting enzyme 2 (ACE2) and/or the SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 spike protein RBD). Nine of these drugs were identified by both screening methods. Three of the identified compounds, Evans blue, sodium lifitegrast, and lumacaftor, were found to inhibit viral replication in a Vero-E6 cell-based SARS-CoV-2 infection assay and may have utility as repurposed therapeutics. All 22 identified compounds provide scaffolds for the development of new chemical entities for the treatment of COVID-19.

Dataset Information

Spike protein receptor-binding domains from SARS-CoV-2 variants of interest bind human ACE2 more tightly than the prototype spike protein.

Publications

Spike protein receptor-binding domains from SARS-CoV-2 variants of interest bind human ACE2 more tightly than the prototype spike protein.

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