Structural and functional analysis of female sex hormones against SARS-CoV-2 cell entry

Jorge Alberto Aguilar-Pineda, Mazen Albaghdadi, Wanlin Jiang, Karin J. Vera-Lopez, Rita Nieto-Montesinos, Karla Lucia F. Alvarez, Gonzalo Davila Del-Carpio, Badhin Gómez, Mark E. Lindsay, Rajeev Malhotra, Christian L.Lino Cardenas

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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 report 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-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, 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.

Original languageEnglish
Article number11508
JournalInternational Journal of Molecular Sciences
Volume22
Issue number21
DOIs
StatePublished - 1 Nov 2021

Keywords

  • ACE2
  • COVID-19
  • Estrogenes
  • Sex hormones

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