Bivalent enzyme inhibitors discovered using dynamic covalent chemistry

Research output: Contribution to journalArticle

  • External authors:
  • Alexandra J. Clipson
  • Venugopal T. Bhat
  • Iain McNae
  • Anne M. Caniard
  • Dominic J. Campopiano

Abstract

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. Library powers: A bivalent dynamic covalent chemistry (DCC) system has been designed to selectively target members of the homodimeric glutathione-S-transferase (GST) enzyme family. The approach (see scheme) yielded compounds with selective, nanomolar affinity and demonstrates that DCC can be used to simultaneously interrogate binding sites on different subunits of a dimeric protein. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bibliographical metadata

Original languageEnglish
Pages (from-to)10562-10570
Number of pages8
JournalChemistry - A European Journal
Volume18
Issue number34
DOIs
StatePublished - 20 Aug 2012