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

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.