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SARS-CoV-2 cell entry beyond the ACE2 receptor.

Shamila D Alipoor1, Mehdi Mirsaeidi2

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SARS-CoV-2 uses multiple cell surface receptors, not just ACE2, for entry. Identifying these receptors offers new therapeutic targets for COVID-19 treatment.

Keywords:
ACE2CD147CD26NeuropilinSARS-CoV-2

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Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Angiotensin-converting enzyme 2 (ACE2) is recognized as the primary entry receptor for SARS-CoV-2.
  • Observed viral tissue tropism and infectivity rates do not consistently correlate with ACE2 expression levels, suggesting other factors are involved.
  • This indicates the potential involvement of additional cellular receptors or accessory membrane proteins in SARS-CoV-2 cell entry.

Purpose of the Study:

  • To systematically identify and review cellular receptors and accessory membrane proteins involved in SARS-CoV-2 cell entry.
  • To explore the implications of these identified entry mechanisms for viral infectivity and potential therapeutic strategies.

Main Methods:

  • A systematic literature search was conducted across PubMed/Medline, EMBASE, and Cochrane Library databases.
  • MeSH terms including "cell entry", "surface receptor", "ACE2", and "SARS-CoV-2" were utilized for the search.
  • Selected English-language studies published up to February 2022 were reviewed.

Main Results:

  • Several receptors and auxiliary membrane proteins, including CD147, NRP-1, CD26, AGTR2, Band3, KREMEN1, ASGR1, ANP, TMEM30A, CLEC4G, and LDLRAD3, were identified as facilitators of SARS-CoV-2 entry, in addition to ACE2.
  • The expression of Band3 protein on erythrocytes and its binding with the SARS-CoV-2 S protein may explain asymptomatic hypoxemia in COVID-19.
  • Different SARS-CoV-2 variants (Alpha, Kappa, Delta, Delta+, Omicron) may exhibit varying binding affinities to these identified receptors.

Conclusions:

  • The high infectivity rate of SARS-CoV-2 is likely attributed to its capacity to utilize a diverse group of cell surface receptors for host cell entry.
  • These identified cell surface receptors represent promising targets for the development of novel therapeutic agents against SARS-CoV-2 infections.