Glucocorticoids Bind to SARS-CoV-2 S1 at Multiple Sites Causing Cooperative Inhibition of SARS-CoV-2 S1 Interaction With ACE2

Frontiers in Immunology

Eugenio Hardy¹  Hassan Sarker²  J. N. Mark Glover²  Rashmi Panigrahi²  Carlos Fernandez-Patron²  Shokrollah Elahi⁵ 

[1] Center of Molecular Immunology, Havana, Cuba;Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada;Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada;Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada;Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada;

关键词: glucocorticoids;    SARS-CoV-2;    ACE2 (angiotensin converting enzyme 2);    innate immunity;    COVID;    coronavirus;   

DOI  :  10.3389/fimmu.2022.906687

来源: DOAJ

【 摘 要 】

Dexamethasone may reduce mortality in COVID-19 patients. Whether dexamethasone or endogenous glucocorticoids, such as cortisol, biochemically interact with SARS-CoV-2 spike 1 protein (S1), or its cellular receptor ACE2, is unknown. Using molecular dynamics (MD) simulations and binding energy calculations, we identified 162 druggable pockets in various conformational states of S1 and all possible binding pockets for cortisol and dexamethasone. Through biochemical binding studies, we confirmed that cortisol and dexamethasone bind to S1. Limited proteolysis and mass spectrometry analyses validated several MD identified binding pockets for cortisol and dexamethasone on S1. Interaction assays indicated that cortisol and dexamethasone separately and cooperatively disrupt S1 interaction with ACE2, through direct binding to S1, without affecting ACE2 catalytic activity. Cortisol disrupted the binding of the mutant S1 Beta variant (E484K, K417N, N501Y) to ACE2. Delta and Omicron variants are mutated in or near identified cortisol-binding pockets in S1, which may affect cortisol binding to them. In the presence of cortisol, we find increased inhibition of S1 binding to ACE2 by an anti-SARS-CoV-2 S1 human chimeric monoclonal antibody against the receptor binding domain. Whether glucocorticoid/S1 direct interaction is an innate defence mechanism that may have contributed to mild or asymptomatic SARS-CoV-2 infection deserves further investigation.

【 授权许可】

Unknown