A dual-responsive AI-designed peptide P9-conjugate disrupts E6-E6AP Interface to restore p53 and suppress HPV16-driven cervical cancer.

Cervical cancer remains a major global health burden in women, mainly driven by persistent infection with high-risk human papillomavirus (hr-HPV). The viral oncoprotein E6 plays an essential role in HPV-related cervical by promoting p53 degradation via interaction with E6AP. However, blocking the E6-E6AP interaction is difficult due to the lack of clear binding pockets and reliance on flexible protein-protein interactions. In this study, we identify a key sequence in E6AP (S372-382) and improve it through AI-assisted structural analysis to generate an optimized peptide (P9) with high affinity for E6. P9 is further conjugated to chemotherapy drug camptothecin (CPT) to form a dual-responsive compound (Comp.1) with enhanced intracellular delivery, disruption of E6-E6AP interaction, and restoration of p53 function. Our work offers an effective and selective way to interfere with HPV-driven cervical cancer and highlights the potential of structure-guided peptide design in HPV16 E6 protein.