Structural and functional analysis of female sex hormones against SARS-Cov2 cell entry

Aguilar-Pineda, Jorge Alberto; Albaghdadi, Mazen; Jiang, Wanlin; Lopez, Karin J. Vera; Del-Carpio, Gonzalo Davila; Valdez, Badhin Gómez; Lindsay, Mark E.; Malhotra, Rajeev; Lino Cardenas, Christian L.

Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further observed that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly estrogens can disrupt glycan-glycan interactions and glycan-protein interactions between the human ACE2 and the SARS-CoV2 thereby blocking its entry into cells. In a mouse model, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.