Improve the Stability and Activity of Antimicrobial Peptides by the Proline-Based PXXP Hinge Structure

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Developing a simple and effective strategy to enhance the stability of antimicrobial peptides (AMPs) is critical for successful AMP design. In this study, we leveraged the property of proline to form hinge-like structures and designed a series of repetitive symmetrical sequence AMPs with different proline-based hinge centers (PWWP, PKKP, and PWKP), proposing a template of (KW) n PXXP(WK) n -NH 2 (where XX = WW, n = 1–4 or XX = KK, WK, n = 2–4). The corresponding templates without hinge structures, (KW) n (WK) n -NH 2 ( n = 1–4), were used as controls. Through comprehensive evaluations of activity, toxicity, and stability, we identified two promising AMP candidates, (KW) 3 PK and (KW) 3 PWK, which demonstrated excellent antibacterial activity, cell selectivity, and stability. Our findings indicate that incorporating a proline-containing PXXP hinge structure into AMP sequences could serve as an effective strategy to enhance AMP stability.