PEGylation of the Antimicrobial Peptide PG-1: A Link between Propensity for Nanostructuring and Capacity of the Antitrypsin Hydrolytic Ability

• Published in: Journal of medicinal chemistry 2021-07, Vol.64 (14), p.10469-10481
• Main Authors: Yu, Weikang, Wang, Jiajun, Wang, Zihang, Li, Lingxue, Li, Wenyu, Song, Jing, Zhang, Shanshan, Shan, Anshan
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00879

The increasing prevalence of antibacterial resistance globally underscores the urgent need for updated antimicrobial peptides (AMPs). Here, we describe a strategy for inducing the self-assembly of protegrin-1 (PG-1) into nanostructured antimicrobial agents with significantly improved pharmacological properties. Our strategy involves PEGylation in the terminals of PG-1 and subsequent self-assembly in aqueous media in the absence of exogenous excipients. Compared with the parent PG-1, the therapeutic index (TI) of NPG750(TIGram‑negative bacteria = 17.07) and CPG2000(TIAll = 26.02) was increased. Importantly, NPG750 and CPG2000 offered higher stability toward trypsin degradation. Mechanistically, NPG750 and CPG2000 exerted their bactericidal activity by membrane-active mechanisms due to which microbes were not prone to develop resistance. Our findings proved PEGylation as a simple yet versatile strategy for generating AMP-derived bioactive drugs with excellent antitrypsin hydrolytic ability and lower cytotoxicity. This provides a theoretical basis for the further clinical application of AMPs.