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

ABSTRACT: Human papillomavirus (HPV) remains a global health burden, yet there are no targeted therapies for HPV-related cancers. The HPV E6 protein is essential for 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 HPV16 E6 protein. Nanobody A5 was fused to Von Hippel-Lindau protein to generate a PROTAC that degrades E6 (PROTAC^E6). Mutational rescue experiments validated E6 degradation via the CRL2^VHL E3 ligase. To deliver PROTAC^E6, we used a clinically viable DNA vaccine, which offers the advantages of localized PRO

SUBMITTER: Smalley TB 

PROVIDER: S-EPMC12582245 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature