Mechanism and structure-activity relationships of norspermidine-based peptidic inhibitors of trypanothione reductase

被引：21

作者：

Dixon, MJ ^{[1
]}

Maurer, RI ^{[1
]}

Biggi, C ^{[1
]}

Oyarzabal, J ^{[1
]}

Essex, JW ^{[1
]}

Bradley, M ^{[1
]}

机构：

[1] Univ Southampton, Sch Chem, Southampton SO17 1BJ, Hants, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2005年 / 13卷 / 14期

基金：

英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;

关键词：

trypanothione reductase; parallel synthesis; mechanism of action; structure-activity relationships;

D O I：

10.1016/j.bmc.2005.04.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A library of polyamine-peptide conjugates based around some previously identified inhibitors of trypanothione reductase was synthesised by parallel solid-phase chemistry and screened. Kinetic analysis of library members established that subtle structural changes altered their mechanism of action, switching between competitive and non-competitive inhibition. The mode of action of the non-competitive inhibitors was investigated in detail by a variety of techniques including enzyme kinetic analysis (looking at both NADPH and trypanothione disulfide substrates), gel filtration chromatography and analytical ultracentrifugation, leading to the identification of an allosteric mode of inhibition. (c) 2005 Published by Elsevier Ltd.

引用

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页码：4513 / 4526

页数：14

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