De Novo Design of Mirror-Image Dimeric Antimicrobial Peptides with Low Drug Resistance and In Vivo Efficacy.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-09-29 DOI:10.1021/acs.jmedchem.5c01375

Jingying Zhang,Anqi Chu,Ping Yang,Xu Ouyang,Beibei Li,Wenbo Mao,Xiaoyan Wu,Chao Zhong,Sanhu Gou,Yun Zhang,Hui Liu,Jingman Ni

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引用次数: 0

Abstract

Dimerization and mirror-image modification are effective strategies for enhancing the antimicrobial activity and stability of antimicrobial peptides (AMPs). However, mirror-image dimeric AMPs, characterized by their mirror-image amino acid sequences and mirror-image stereocenters within a single peptide, have been rarely reported. In this study, 19 mirror-image dimeric AMPs and 2 all d-/l-type AMPs are designed and synthesized to investigate their structure-activity relationships. Peptides with YYYXXxxyyy or yyyxxXXYYY sequences (X/Y represents cationic/hydrophobic residues, x/y denotes d-type residues) possess favorable bacterial selectivity. The superior peptide M-WL-D/L exhibits potent activity against multidrug-resistant bacteria, a low propensity for drug resistance, favorable stability, robust membrane disruption, high DNA affinity, and immunoregulatory activity. Notably, M-WL-D/L demonstrates in vivo half-lives of 22.4 min (5 mg/kg) and 20.7 min (10 mg/kg), along with effective in vivo efficacy and satisfactory safety. This innovative AMP design strategy, with M-WL-D/L as a standout candidate, offers a promising avenue for combating multidrug-resistant bacteria.

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具有低耐药性和体内有效性的镜像二聚体抗菌肽的从头设计。

二聚化和镜像修饰是提高抗菌肽抗微生物活性和稳定性的有效策略。然而，镜像二聚体amp，其特点是其氨基酸序列和镜像立体中心在一个肽内，很少被报道。本研究设计合成了19种镜像二聚体AMPs和2种全d-/l型AMPs，研究了它们的构效关系。具有YYYXXxxyyy或YYYXXxxyyy序列的肽（X/Y表示阳离子/疏水残基，X/Y表示d型残基）具有良好的细菌选择性。优越的肽M-WL-D/L对多重耐药细菌具有强大的活性，耐药倾向低，稳定性好，强大的膜破坏，高DNA亲和力和免疫调节活性。值得注意的是，M-WL-D/L的体内半衰期分别为22.4 min （5 mg/kg）和20.7 min (10 mg/kg)，具有有效的体内疗效和令人满意的安全性。这种创新的AMP设计策略，以M-WL-D/L为突出的候选药物，为对抗多药耐药细菌提供了一条有希望的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.