Targeted degradation of the HPV oncoprotein E6 reduces tumor burden in cervical cancer.

ABSTRACT: Human Papilloma Virus (HPV)-related cancers are a global health burden, yet there are no targeted therapies available for chronically infected patients. The HPV protein E6 is essential for HPV-mediated tumorigenesis and immune evasion, making it an attractive target for antiviral drug development. In this study, we developed an E6-targeting Proteolysis Targeting Chimera (PROTAC) that inhibits the growth of HPV(+) tumors. To develop E6 antagonists, we generated a panel of nanobodies targeting E6 proteins derived from the oncogenic HPV16 subtype. The highest affinity E6 nanobody, A5, was fused to Von Hippel Lindau protein (VHL) to generate a PROTAC that degrades E6 (PROTAC^E6). Mutational rescue experiments validated specific degradation via the CRL2^VHL E3 ligase. Intral

SUBMITTER: Smalley TB 

PROVIDER: S-EPMC11507957 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature