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VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation

Kyle Mangano1, Robert G Guenette2, Spencer Hill2

  • 1Induced Proximity Platform, Amgen Research, Thousand Oaks, CA 91320, USA; Amgen R&D Postdoctoral Fellows Program, Thousand Oaks, CA 91320, USA.

Cell Chemical Biology
|March 6, 2025
PubMed

Insights

Viral E3 ligases offer targeted protein degradation in diseased cells. Viral E3 pan-essential removing targeting chimeras (VIPER-TACs) selectively degrade proteins, enhancing therapeutic windows and reducing toxicity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Targeted protein degradation (TPD) uses E3 ubiquitin ligases to degrade proteins.
  • Current TPD therapies face toxicity due to broad E3 ligase expression in healthy tissues.
  • Viral E3 ligases (vE3s) are expressed only in diseased cells, offering a potential solution.

Purpose of the Study:

  • To introduce viral E3 pan-essential removing targeting chimeras (VIPER-TACs) as a novel therapeutic strategy.
  • To demonstrate the selective degradation of essential proteins in diseased cells using VIPER-TACs.
  • To explore the potential of VIPER-TACs in cancer therapy.

Main Methods:

  • Development of bi-functional VIPER-TAC molecules.
  • Utilizing human papillomavirus (HPV) E6 ligase as a vE3.
  • Testing VIPER-TACs in a model of HPV-positive cervical cancer targeting a pan-essential protein.

Main Results:

  • Proof-of-concept for VIPER-TACs achieved.
  • HPV E6 ligase successfully degraded a pan-essential target protein.
  • Selective killing of E6-expressing cancer cells demonstrated.

Conclusions:

  • VIPER-TACs selectively degrade essential proteins in diseased cells.
  • This approach significantly increases the therapeutic window and reduces toxicity.
  • VIPER-TACs expand the potential applications of TPD in cancer treatment.
Keywords:
HPV positive cancerVIPER-TACantiviralbiotechnologychemical biologyinduced proximitytargeted protein degradationviral E3 ligase

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