Modifying Antimicrobial Peptides with Albumin-Binding Molecules Enhances Membrane-Disrupting Efficacy by Modulating the Secondary Structure

作者：Yang Zhou, Juhong Wu, Haili Lin, Meiru Song, Lina Deng, Yuhan Mai, Zhiyou Wang, Nannan Zeng, Wei Zhang, Yichang Liu, Longguang Jiang, Cai Yuan, Mingdong Huang, Jinyu Li, Peng Xu · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00407 · 被引用次数：5 · 研究领域：Antimicrobial Peptides and Activities、Lipid Membrane Structure and Behavior、Biochemical and Structural Characterization

Antimicrobial peptides (AMPs) are powerful tools in combating drug-resistant bacteria. However, their clinical application is hindered by poor pharmacokinetics and suboptimal antimicrobial activity. This study proposes a strategy to enhance the antimicrobial activity and biosafety of AMPs by modification with albumin-binding molecules (ABMs). This strategy was validated by employing two model peptides with moderate antimicrobial efficacy. First, ABM modification stabilizes the secondary structures, facilitating bacterial membrane disruption. Additionally, modified AMPs target albumin in blood vessels, reducing renal clearance in vivo. Moreover, this binding minimizes contact with blood and endothelial cells, consequently diminishing vascular toxicity without compromising antimicrobial activity. Molecular dynamic simulations followed by experimental validation revealed new molecular insights into the mechanism underlying AMP-mediated membrane disruption, confirming our design strategy. This dual mechanism, structural stabilization and albumin-mediated pharmacokinetic enhancement, addresses the key limitation of AMPs, offering a versatile approach to develop potent, systemically safe antimicrobial therapies.