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Abemaciclib restricts HCMV replication by suppressing pUL97-mediated phosphorylation of SAMHD1

Georgios Vavouras Syrigos1, Maximilian Feige1, Alicia Dirlam1

  • 1Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany.

Antiviral Research
|July 29, 2023
PubMed

Insights

FDA-approved CDK inhibitors show promise as antivirals against human cytomegalovirus (HCMV). These drugs block viral kinase pUL97 from inactivating the antiviral factor SAMHD1, offering a new therapeutic strategy.

Area of Science:

  • Virology
  • Immunology
  • Pharmacology

Background:

  • Human cytomegalovirus (HCMV) poses significant risks to newborns and immunocompromised individuals.
  • HCMV replication involves interactions with host cell factors, including cyclin-dependent kinases (CDKs).
  • HCMV encodes the viral kinase pUL97, a CDK homolog, which antagonizes the antiviral factor SAMHD1 through phosphorylation.

Purpose of the Study:

  • To investigate the therapeutic potential of FDA-approved CDK inhibitors (CDKIs) as antivirals against HCMV.
  • To determine if CDKIs can prevent HCMV-mediated inactivation of SAMHD1.
  • To establish SAMHD1 as a therapeutic target for HCMV infections.

Main Methods:

  • Analysis of SAMHD1 inactivation kinetics post-HCMV infection in macrophages.
  • Testing of CDKIs for antiviral activity against HCMV.
  • Assessment of the ability of CDKIs to block pUL97-mediated SAMHD1 phosphorylation.

Main Results:

  • HCMV pUL97 phosphorylates and inactivates SAMHD1 early after macrophage infection.
  • Abemaciclib, a second-generation CDKI, demonstrated potent antiviral activity against HCMV.
  • The antiviral effect of Abemaciclib was primarily attributed to its inhibition of pUL97-mediated SAMHD1 phosphorylation.

Conclusions:

  • Clinically approved CDKIs represent a promising therapeutic avenue for HCMV infections.
  • Inhibiting pUL97-mediated SAMHD1 inactivation is a viable antiviral strategy.
  • SAMHD1 is identified as a potent and effective therapeutic target against HCMV.

Keywords:
AbemaciclibCDK inhibitorsHCMVLDC4297SAMHD1pUL97

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