VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation.
Kyle Mangano, Robert G Guenette, Spencer Hill, Shiqian Li, Jeffrey J Liu, Cory M Nadel, Suresh Archunan, Arghya Sadhukhan, Rajiv Kapoor, Seung Wook Yang, Kate S Ashton, Patrick Ryan Potts
Author Information
Kyle Mangano: Induced Proximity Platform, Amgen Research, Thousand Oaks, CA 91320, USA; Amgen R&D Postdoctoral Fellows Program, Thousand Oaks, CA 91320, USA.
Robert G Guenette: Induced Proximity Platform, Amgen Research, Thousand Oaks, CA 91320, USA.
Spencer Hill: Induced Proximity Platform, Amgen Research, Thousand Oaks, CA 91320, USA.
Shiqian Li: Induced Proximity Platform, Amgen Research, Thousand Oaks, CA 91320, USA.
Jeffrey J Liu: Discovery Proteomics, Amgen Research, Thousand Oaks, CA 91320, USA.
Cory M Nadel: Induced Proximity Platform, Amgen Research, Thousand Oaks, CA 91320, USA.
Suresh Archunan: SARC - Syngene Amgen Research & Development Center, Bengaluru 560099, India.
Arghya Sadhukhan: SARC - Syngene Amgen Research & Development Center, Bengaluru 560099, India.
Rajiv Kapoor: SARC - Syngene Amgen Research & Development Center, Bengaluru 560099, India.
Seung Wook Yang: Induced Proximity Platform, Amgen Research, Thousand Oaks, CA 91320, USA.
Kate S Ashton: Medicinal Chemistry, Amgen Research, Thousand Oaks, CA 91320, USA.
Patrick Ryan Potts: Induced Proximity Platform, Amgen Research, Thousand Oaks, CA 91320, USA. Electronic address: ryan.potts@amgen.com.
In targeted protein degradation (TPD) a protein of interest is degraded by chemically induced proximity to an E3 ubiquitin ligase. One limitation of using TPD therapeutically is that most E3 ligases have broad tissue expression, which can contribute to toxicity via target degradation in healthy cells. Many pathogenic and oncogenic viruses encode E3 ligases (vE3s), which de facto have strictly limited expression to diseased cells. Here, we provide proof-of-concept for viral E3 pan-essential removing targeting chimeras (VIPER-TACs) that are bi-functional molecules that utilize viral E3 ubiquitin ligases to selectively degrade pan-essential proteins and eliminate diseased cells. We find that the human papillomavirus (HPV) ligase E6 can degrade the SARS1 pan-essential target protein in a model of HPV-positive cervical cancer to selectively kill E6 expressing cancer cells. Thus, VIPER-TACs have the capacity to dramatically increase the therapeutic window, alleviate toxicity concerns, and ultimately expand the potential target space for TPD.
