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

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

Posted 29 Jul 2020
bioRxiv DOI: 10.1101/2020.07.29.227249

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. ### Competing Interest Statement The authors have declared no competing interest.

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