Structural Optimization of Cn-AMP1 Enhances Antibacterial and Anticancer Potency With Low Hemolysis.

Antimicrobial peptides (AMPs) represent promising scaffolds for therapeutic development, but many natural sequences show limited potency or poor selectivity. Among them, Cn-AMP1, a coconut-derived peptide, exhibits excellent biocompatibility but weak antibacterial and anticancer activities owing to low hydrophobicity and minimal cationic charge. Here, we rationally designed a series of Cn-AMP1 derivatives with systematic modulation of charge and hydrophobicity to probe structure-activity relationships. Among them, CAP10, displayed 2-4-fold stronger antibacterial potency than earlier analogs while maintaining hemolysis below 10%. CAP10 also achieved measurable cytotoxicity toward cancer cells, representing a clear improvement over the other Cn-AMP1 derivatives. Molecular dynamics simulations revealed that CAP10 penetrates deeply into bacterial and cancer membranes, inducing local bilayer thinning and density depletion, whereas Cn-AMP1 remained surface-bound with limited disruption. These results establish that simultaneous optimization of hydrophobicity and charge enhances membrane-active selectivity and dual functionality. Our findings provide structural principles for the rational design of next-generation AMPs with improved efficacy and safety profiles.