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Updated: Jan 11, 2026

Evaluation of the Efficacy And Toxicity of RNAs Targeting HIV-1 Production for Use in Gene or Drug Therapy
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Evaluation of the Efficacy And Toxicity of RNAs Targeting HIV-1 Production for Use in Gene or Drug Therapy

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A potent and selective PROTAC degrader of CDK9 as effective inhibitor of HIV-1 RNA synthesis

Bo Yang1, Ling Ma1,2, Xiaotang Yang1

  • 1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

Molecular Diversity
|November 12, 2025
PubMed

Insights

Researchers developed a novel PROTAC degrader targeting Cyclin-dependent kinase 9 (CDK9) to combat HIV-1. This selective approach reduces viral replication with lower toxicity, offering a promising new antiviral strategy.

Area of Science:

  • Molecular Biology
  • Virology
  • Medicinal Chemistry

Background:

  • Cyclin-dependent kinase (CDK) 9 is crucial for HIV-1 transcription elongation.
  • Developing specific CDK9 inhibitors is challenging due to high CDK family homology, leading to off-target toxicities.
  • Proteolysis-targeting chimeras (PROTACs) offer a strategy for targeted protein degradation.

Purpose of the Study:

  • To design and synthesize novel heterobifunctional compounds as selective CDK9 degraders.
  • To evaluate the efficacy and safety of a VHL-recruiting PROTAC compound against HIV-1.
  • To explore the potential of PROTACs for developing broad-spectrum antiviral agents.

Main Methods:

  • Synthesis of heterobifunctional compounds conjugating a CDK inhibitor with an E3 ligase ligand.
  • Identification of a selective CDK9 PROTAC degrader (compound 9g) using western blotting and MS-based proteomics.
  • Assessment of anti-HIV-1 activity, RNA synthesis inhibition, and cytotoxicity in vitro.

Main Results:

  • Compound 9g was identified as a highly selective PROTAC degrader of CDK9.
  • The PROTAC compound effectively reduced HIV-1 RNA synthesis by inhibiting CDK9-mediated transcription.
  • Compound 9g demonstrated significantly lower cytotoxicity and a higher anti-HIV-1 therapeutic index compared to its warhead.

Conclusions:

  • A selective CDK9-targeted degrader was successfully developed, serving as a novel anti-HIV-1 lead compound.
  • The PROTAC approach shows potential for creating host-directed, broad-spectrum antiviral agents.
  • Targeted protein degradation offers an effective strategy to overcome challenges in developing specific kinase inhibitors for antiviral therapy.

Keywords:
2-(4-sulfamoylphenyl)amino-pyrrolo[2,3-d]pyrimidineAntiviralCDK9HIV-1PROTAC

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