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CDK4/6 inhibitor palbociclib promotes SARS-CoV-2 cell entry by down-regulating SKP2 dependent ACE2 degradation

Yingzi Xiao1, Ying Yan2, Le Chang2

  • 1National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital / National Center of Gerontology, Beijing, PR China; National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, PR China; Beijing Engineering Research Center of Laboratory Medicine, Beijing, PR China.

Antiviral Research
|February 22, 2023
PubMed

Insights

Palbociclib and other cell cycle arresting drugs increase angiotensin-converting enzyme 2 (ACE2) expression. This enhanced ACE2 expression facilitates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry, suggesting these drugs may not be suitable for COVID-19 treatment.

Area of Science:

  • Virology
  • Cell Biology
  • Pharmacology

Background:

  • The COVID-19 pandemic necessitates exploring repurposed drugs for treatment.
  • Angiotensin-converting enzyme 2 (ACE2) is the primary receptor for SARS-CoV-2 entry.
  • Palbociclib, a CDK4/6 inhibitor, was identified as a potential repurposed drug for COVID-19.

Purpose of the Study:

  • To investigate the effect of palbociclib and other cell cycle arresting agents on ACE2 expression.
  • To elucidate the mechanism by which palbociclib influences ACE2 levels.
  • To assess the implications of altered ACE2 expression for SARS-CoV-2 infection.

Main Methods:

  • Cell cycle analysis using flow cytometry.
  • Quantitative real-time PCR (qRT-PCR) for ACE2 mRNA quantification.
  • Western blotting for ACE2 protein level assessment.
  • Immunofluorescence microscopy for ACE2 subcellular localization.
  • Ubiquitin-proteasome and lysosomal degradation assays.
  • Pseudotyped SARS-CoV-2 infection assays.

Main Results:

  • Palbociclib and other cell cycle arresting compounds induced G0/G1 phase arrest.
  • These compounds significantly up-regulated ACE2 mRNA and protein levels without changing its localization.
  • Palbociclib inhibited ACE2 degradation by down-regulating S-phase kinase-associated protein 2 (SKP2).
  • Increased ACE2 expression facilitated pseudotyped SARS-CoV-2 infection.

Conclusions:

  • ACE2 expression is inversely correlated with cell proliferation.
  • Cell cycle arresting agents enhance ACE2 expression and SARS-CoV-2 cell entry.
  • Palbociclib and similar compounds may not be suitable for treating SARS-CoV-2 infection due to increased viral entry.
Keywords:
ACE2Cell cycleCell proliferationDegradationPalbociclibSARS-CoV-2SKP2

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