Improving the Antimicrobial Activity of an Amyloidogenic Aβ Peptide Through Additional Fragments.

Given the similarities of action mechanism between amyloidogenic peptides (e.g. Aβ) and antimicrobial peptides (AMPs), we rationally engineered an amyloidogenic Aβ peptide to improve its antimicrobial activity: the aggregation-prone fragment was reverse-repeated to increase antimicrobial activity; poly-arginine (R) was flanked to both ends of the repeated fragments to enhance membrane interaction and inhibit amyloidogenesis; a β-turn fragment (DPDG/YNGK) was inserted between the repeated fragments to inhibit amyloidogenesis. Antimicrobial assays demonstrated that the designed peptides exhibited significantly enhanced antimicrobial activity. Among the designed peptides, Aβ-6R-YNGK, Aβ-6R-YNGK-r, Aβ-10R-YNGK, and Aβ-10R-YNGK-r exhibited potent antimicrobial activity, particularly against Staphylococcus epidermidis with MICs of 5, 5, 5, and 1 µM, respectively. Moreover, at 20 µM, these peptides showed significant anticancer activity and low cytotoxicity, reducing U937 human lymphoma cell viability to below 30% while maintaining over 80% viability of human microglial HMC3 cell. Our rational design approach provides a novel strategy for engineering antimicrobial peptide. The designed antimicrobial peptides Aβ-6R-YNGK, Aβ-6R-YNGK-r, Aβ-10R-YNGK, and Aβ-10R-YNGK-r hold promise as a new class of antimicrobial/cancer agents.