抗革兰阴性菌新靶标:脂多糖转运蛋白LptDE及其抑制剂研究进展  

Novel antibacterial drug target against Gram-negative bacteria:lipopolysaccharide transport protein LptDE and its inhibitors

作　　者：李玥 李国庆[2] 田元元 李聪然[2] 杨信怡[2] 姚开虎 游雪甫[2] LI Yue;LI Guo-qing;TIAN Yuan-yuan;LI Cong-ran;YANG Xin-yi;YAO Kai-hu;YOU Xue-fu(National Center for Children's Health/Beijing Children's Hospital,Capital Medical University/Beijing Pediatric Research Institute/National Clinical Research Center for Respiratory Diseases/Key Laboratory of Major Diseases in Children,Ministry of Education/Beijing Key Laboratory of Pediatric Respiratory Infection Diseases,Beijing 100045,China;Beijing Key Laboratory of Antimicrobial Agents,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;Department of Dermatology,National Center for Children's Health/Beijing Children's Hospital,Capital Medical University,Beijing 100045,China)

机构地区：[1]国家儿童医学中心/首都医科大学附属北京儿童医院/北京市儿科研究所/国家呼吸系统疾病临床医学研究中心/教育部儿科重大疾病研究重点实验室/儿童呼吸道感染性疾病研究北京市重点实验室,北京100045 [2]中国医学科学院,北京协和医学院医药生物技术研究所,抗感染药物研究北京市重点实验室,北京100050 [3]国家儿童医学中心/首都医科大学附属北京儿童医院皮肤科,北京100045

出　　处：《药学学报》2024年第2期279-288,共10页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82204465)。

摘　　要：富含脂多糖(lipopolysaccharide,LPS)的外膜是绝大多数革兰阴性(Gram-negative,G-)菌生存必需的生物学屏障。LPS转运蛋白(lipopolysaccharide transport protein,Lpt)复合体LptDE负责LPS转运和外膜组装的最后关键一步,在G-菌中普遍存在且结构-功能较为保守,哺乳动物细胞中缺乏同源蛋白,是颇具开发前景的抗菌新靶标。近10年,LptDE蛋白三维结构的破译为基于此类“非酶”蛋白靶标的药物发现奠定了基础,首个作用于LptD的拟肽类化合物murepavadin开启了一类新作用机制的抗菌药物研究。本文将总结LptDE的分子特征、结构-功能,梳理murepavadin等新型拟肽类抗菌药物的研究进展,以期为相关研究提供参考。The outer membrane composed predominantly of lipopolysaccharide(LPS)is an essential biological barrier for most Gram-negative(G-)bacteria.Lipopolysaccharide transport protein(Lpt)complex LptDE is responsible for the critical final stage of LPS transport and outer membrane assembly.The structure and function of LptDE are highly conserved in most G-bacteria but absent in mammalian cells,and thus LptDE complex is regarded as an attractive antibacterial target.In recent 10 years,the deciphering of the three-dimensional structure of LptDE protein facilities the drug discovery based on such"non-enzyme"proteins.Murepavadin,a peptidomimetic compound,was reported to be the first compound able to target LptD,enlightening a new class of antibacterial molecules with novel mechanisms of action.This article is devoted to summarize the molecular characteristics,structure-function of LptDE protein complex and review the development of murepavadin and related peptidomimetic compounds,in order to provide references for relevant researches.

关 键 词：革兰阴性菌 脂多糖外膜 脂多糖转运蛋白复合体DE 抗菌新靶标 新型拟肽类抗菌药物 

分 类 号：R966[医药卫生—药理学]