Work

Overcoming Clinical Barriers: Utilizing Self‐Assembly Systems to Break the Protease Limitations of Antimicrobial Peptides

Year: 2025

Type: article

Abstract: ABSTRACT Natural antimicrobial peptides (AMPs) encounter significant challenges in transitioning to clinical application, primarily due to low bioactivity, high toxicity, and poor stability. This study proposes a strategy to enhance the stability of AMPs through molecular assembly while exploring the advantages of the newly designed self‐assembled peptides compared to unimer peptides. We conducted a comprehensive investigation of antimicrobial activity, biocompatibility, in vitro stability, and particularly protease stability, aiming to develop highly efficient and stable designer peptides as alternatives to traditional antibiotics. A series of designer peptides with self‐assembling capabilities was constructed by attaching various hydrophobic scaffolds to an enzyme‐resistant short peptide sequence. The self‐assembled designer peptide Pba* with 1‐pyrenebutyric acid (Pba) as the hydrophobic scaffold exhibited the highest antibacterial activity (GM MIC = 2.88) and the greatest clinical potential (GM SI = 44.44), while maintaining excellent biocompatibility and physiological stability. Mechanistic studies revealed that Pba* self‐assembled into spherical micelles and nanofibers, trapping bacteria and disrupting cell membranes, interfering with respiration and energy metabolism. Notably, Pba* displayed negligible toxicity and alleviated bacterial infections in mice. This study paves the way for the development of highly effective antimicrobial materials.

Source: Aggregate

DOI: 10.1002/agt2.70193