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SARS-CoV-2 hijacks cellular kinase CDK2 to promote viral RNA synthesis

Saisai Guo1, Xiaobo Lei2, Yan Chang3

  • 1Department of Immunology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Signal Transduction and Targeted Therapy
|December 27, 2022
PubMed

Insights

Researchers identified Cyclin-dependent kinase 2 (CDK2) as a crucial host factor for SARS-CoV-2 RNA replication. CDK2 inhibition effectively reduces viral RNA synthesis and infection, highlighting it as a promising target for new antiviral drugs.

Area of Science:

  • Virology
  • Molecular Biology
  • Drug Discovery

Background:

  • The COVID-19 pandemic underscores the urgent need for broad-spectrum antiviral therapies.
  • Identifying host factors essential for SARS-CoV-2 replication is key to developing effective treatments and pandemic preparedness.

Purpose of the Study:

  • To identify host proteins interacting with SARS-CoV-2 nonstructural protein 12 (nsp12), the RNA-dependent RNA polymerase (RdRp).
  • To investigate the role of identified host factors in viral RNA synthesis and SARS-CoV-2 infection.
  • To evaluate potential therapeutic targets for antiviral drug development.

Main Methods:

  • Mass spectrometry (MS)-based proteomics was employed to identify host proteins associated with SARS-CoV-2 nsp12.
  • The interaction between CDK2 and nsp12 was confirmed, and nsp12 phosphorylation at T20 by CDK2 was analyzed.
  • The effect of CDK2 inhibitors on viral RNA synthesis and SARS-CoV-2 infection was assessed.

Main Results:

  • Host protein Cyclin-dependent kinase 2 (CDK2) was identified as a nsp12-interacting protein.
  • CDK2 facilitates the assembly of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) complex (nsp12, nsp7, nsp8) by phosphorylating nsp12 at T20.
  • CDK2 promotes efficient viral RNA synthesis and SARS-CoV-2 infection.
  • CDK2 inhibitors significantly impair viral RNA synthesis and reduce SARS-CoV-2 infection.

Conclusions:

  • CDK2 is a critical host factor for SARS-CoV-2 RNA replication and RdRp complex formation.
  • CDK2 represents a promising therapeutic target for the development of novel SARS-CoV-2 antiviral drugs.

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