Bivalent Enzyme Inhibitors Discovered Using Dynamic Covalent Chemistry

被引：37

作者：

Clipson, Alexandra J. ^{[2
]}

Bhat, Venugopal T. ^{[1
]}

McNae, Iain ^{[2
]}

Caniard, Anne M. ^{[2
]}

Campopiano, Dominic J. ^{[2
]}

Greaney, Michael F. ^{[1
]}

机构：

[1] Univ Manchester, Sch Chem, Manchester M13 9PL, Lancs, England

[2] Univ Edinburgh, Sch Chem, Edinburgh EH9 3JJ, Midlothian, Scotland

来源：

CHEMISTRY-A EUROPEAN JOURNAL | 2012年 / 18卷 / 34期

基金：

英国工程与自然科学研究理事会;

关键词：

drug design; dynamic covalent chemistry; enzymes; hydrazones; inhibitors; GLUTATHIONE-S-TRANSFERASE; PI CLASS GLUTATHIONE; MASS-SPECTROMETRY LEADS; COMBINATORIAL LIBRARIES; NUCLEOPHILIC CATALYSIS; BINDING-SITE; DRUG-RESISTANCE; ETHACRYNIC-ACID; AMPLIFICATION; GENERATION;

D O I：

10.1002/chem.201201507

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

A bivalent dynamic covalent chemistry (DCC) system has been designed to selectively target members of the homodimeric glutathione-S-transferase (GST) enzyme family. The dynamic covalent libraries (DCLs) use aniline-catalysed acylhydrazone exchange between bivalent hydrazides and glutathione-conjugated aldehydes and the bis-hydrazides act as linkers to bridge between each glutathione binding site. The resultant DCLs were found to be compatible and highly responsive to templating with different GST isozymes, with the best results coming from the M and Schistosoma japonicum (Sj) class of GSTs, targets in cancer and tropical disease, respectively. The approach yielded compounds with selective, nanomolar affinity (Ki=61 nM for mGSTM1-1) and demonstrates that DCC can be used to simultaneously interrogate binding sites on different subunits of a dimeric protein.

引用

页码：10562 / 10570

页数：9

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