基于结构的肽脱甲酰基酶大环抑制剂设计

Structure-based design of a macrocyclic inhibitor for peptide deformylase.

作者信息

Hu Xubo, Nguyen Kiet T, Verlinde Christophe L M J, Hol Wim G J, Pei Dehua

机构信息

Department of Chemistry and Ohio State Biochemistry Program, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, USA.

出版信息

J Med Chem. 2003 Aug 28;46(18):3771-4. doi: 10.1021/jm034113f.

DOI:10.1021/jm034113f

PMID:12930137

Abstract

A macrocyclic, peptidomimetic inhibitor of peptide deformylase was designed by covalently cross-linking the P1' and P3' side chains. The macrocycle, which contains an N-formylhydroxylamine side chain as the metal-chelating group, was synthesized from a diene precursor via olefin metathesis using Grubbs's catalyst. The cyclic inhibitor showed potent inhibitory activity toward Escherichia coli deformylase (K(I) = 0.67 nM) and antibacterial activity against both Gram-positive and Gram-negative bacteria (MIC = 0.7-12 microg/mL).

摘要

通过将P1'和P3'侧链共价交联，设计了一种大环肽模拟物肽脱甲酰基酶抑制剂。该大环化合物含有一个作为金属螯合基团的N-甲酰基羟胺侧链，它由二烯前体通过使用格拉布催化剂的烯烃复分解反应合成。该环状抑制剂对大肠杆菌肽脱甲酰基酶表现出强效抑制活性（抑制常数K(I)=0.67 nM），并且对革兰氏阳性菌和革兰氏阴性菌均具有抗菌活性（最低抑菌浓度MIC=0.7 - 12μg/mL）。