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.

Automated summary

In this study, an anticancer AMP (Mastoparan) and its derivatives were designed and evaluated. Preliminary studies showed that the Mastoparan analogue KM8 exhibited selective antitumor effects but had metabolic instability. By substituting the 9Ala residue in KM8, a long-acting derivative KM8-Aib was generated, which showed higher metabolic stability, potent anticancer activity, and lower toxicity. Therefore, KM8-Aib is suggested as a potential antimalignant agent for further study.