Wei Zhang, Lizhen Yuan, Rui Liu, Yanbo Jing, Shijun Lin, Hao Fang, Yuxuan Li, Xiaohui Zhang, Jun Dai, Tao Liu, Fan Xia, and Xiaoding Lou
Journal of the American Chemical Society 2025
DOI: 10.1021/jacs.5c07041
Peptides have demonstrated great potential in drug development. However, their broader application in modalities such as proteolysis-targeting chimeras (PROTACs) remains limited by the lack of real-time efficacy feedback and poor pharmacokinetic stability. Herein, we develop a covalent self-reporting peptide degrader (Co-SPeD) by integrating a fluorine-substituted aryl fluorosulfate warhead and a rotor fluorophore derived from stilbene derivatives, which allows for covalent binding to target proteins via sulfur(VI) fluoride exchange chemistry and emitting activatable fluorescence. Co-SPeD is found to covalently bind to the K51 residue of the MDM2 protein, enabling real-time monitoring of targeted MDM2 degradation. By swapping the targeting peptide and screening rotor fluorophores, the Co-SPeD platform is successfully extended to other oncogenic proteins, including BCL-xL, GRP78, and KRAS (G12D). Additionally, Co-SPeD demonstrates significant antitumor efficacy in preclinical tumor models. More importantly, real-time in vivo monitoring of MDM2 degradation using Co-SPeD plays a crucial role in guiding cisplatin combination administration, leading to a 50% increase in tumor growth inhibition compared to nonguided treatment groups. This approach provides a targeted endogenous protein degradation strategy with real-time monitoring, offering a powerful and generalizable platform for next-generation PROTAC design, the advancement of peptide-based therapeutics, and the rational optimization of cancer therapy.
