Plasma metabolites-based design of long-acting peptides and their anticancer evaluation

Antimicrobial peptides (AMPs) are generally small cationic amphipathic peptides, which are thought to be ideal antineoplastic agents, owing to their favorable selectivity to cancer cells and the ability to overcome drug-resistance. In this study, an anticancer AMP (Mastoparan (INLKALAALAKKIL-NH2)) was selected as the lead compound and a series of Mastoparan derivatives were designed. Preliminary studies verified that an analogue of Mastoparan, KM8 (KLLKINLKALAALAKKIL-NH2), exhibited prominent selective antitumor effects. Instead, it presents a significant defect of metabolic instability, with a half-life in plasma of only about 0.5 h. Metabolite profiling of KM8 was performed and indicated the structure ₉AL₁₀ in peptide sequence could be the fragile site for KM8. Thus, the Aib (unnatural amnio acid) was employed to substitute the ₉Ala residue in KM8, and generating a long-acting KM8 derivative, namely KM8-Aib. Further investigations revealed KM8-Aib possessed higher metabolic stability, more potent anticancer activity in vitro & in vivo, and lower toxicity. Therefore, KM8-Aib is suggested be a potential antimalignant agent that worthy of more in-depth study.