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

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)nPXXP(WK)n-NH2 (where XX = WW, n = 1–4 or XX = KK, WK, n = 2–4). The
corresponding templates without hinge structures, (KW)n(WK)n-NH2 (n = 1–4), were used as controls. Through comprehensive
evaluations of activity, toxicity, and stability, we identified two
promising AMP candidates, (KW)3PK and (KW)3PWK,
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.