Oncolytic peptides represent promising novel candidates for anticancer treatments. In our efforts to develop oncolytic peptides possessing both high protease stability and durable anticancer efficiency, three rounds of optimization were conducted on the first-in-class oncolytic peptide LTX-315. The robust synthetic method, in vitro and in vivo anticancer activity, and anticancer mechanism were investigated. The D-type peptides represented by FXY-12 possessed significantly improved proteolytic stability and sustained anticancer efficiency. Strikingly, the novel hybrid peptide FXY-30, containing one FXY-12 and two camptothecin moieties, exhibited the most potent in vitro and in vivo anticancer activities. The mechanism explorations indicated that FXY-30 exhibited rapid membranolytic effects and induced severe DNA double-strand breaks to trigger cell apoptosis. Collectively, this study not only established robust strategies to improve the stability and anticancer potential of oncolytic peptides but also provided valuable references for the future development of D-type peptides-based hybrid anticancer chemotherapeutics.
Feiyu Li,Bocheng Xu,Zijie Lu,Jiafei Chen,Yike Fu,Jie Huang,Yizhen Wang,Xiang Li
Developing novel substances to synergize with nanozymes is a challenging yet indispensable task to enable the nanozyme-based therapeutics to tackle individual variations in tumor physicochemical properties. The advancement of machine learning (ML) has provided a useful tool to enhance the accuracy and efficiency in developing synergistic substances. In this study, ML models to mine low-cytotoxicity oncolytic peptides are applied. The filtering Pipeline is constructed using a traversal design and the Autogluon framework. Through the Pipeline, 37 novel peptides with high oncolytic activity against cancer cells and low cytotoxicity to normal cells are identified from a library of 25,740 sequences. Combining dataset testing with cytotoxicity experiments, an 80% accuracy rate is achieved, verifying the reliability of ML predictions. Peptide C2 is proven to possess membranolytic functions specifically for tumor cells as targeted by Pipeline. Then Peptide C2 with CoFe hollow hydroxide nanozyme (H-CF) to form the peptide/H-CF composite is integrated. The new composite exhibited acid-triggered membranolytic function and potent peroxidase-like (POD-like) activity, which induce ferroptosis to tumor cells and inhibits tumor growth. The study suggests that this novel ML-assisted design approach can offer an accurate and efficient paradigm for developing both oncolytic peptides and synergistic peptides for catalytic materials.
危险品化学品经营许可证（带存储）