Mechanisms of SARS-CoV-2 entry into cells

Nat Rev Mol Cell Biol. 2022 Jan;23(1):3-20. doi: 10.1038/s41580-021-00418-x. Epub 2021 Oct 5.


The unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response. Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion. We define the roles of furin-like proteases, transmembrane protease, serine 2 (TMPRSS2) and cathepsin L in these processes, and delineate the features of ACE2 orthologues in reservoir animal species and S protein adaptations that facilitate efficient human transmission. We also examine the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. Finally, we present key outstanding questions associated with this critical process.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Evolution, Molecular
  • Humans
  • Membrane Fusion
  • Peptidyl-Dipeptidase A / metabolism
  • SARS-CoV-2 / immunology
  • SARS-CoV-2 / physiology*
  • Viral Proteins / chemistry
  • Viral Proteins / metabolism
  • Virus Internalization*


  • Viral Proteins
  • Peptidyl-Dipeptidase A