Structural Optimization of Cn‐ <scp>AMP1</scp> 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.