Bivalent enzyme inhibitors discovered using dynamic covalent chemistry

Alexandra J. Clipson, Venugopal T. Bhat, Iain McNae, Anne M. Caniard, Dominic J. Campopiano, Michael F. Greaney

    Research output: Contribution to journalArticlepeer-review

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

    Keywords

    • drug design
    • dynamic covalent chemistry
    • enzymes
    • hydrazones
    • inhibitors

    Fingerprint

    Dive into the research topics of 'Bivalent enzyme inhibitors discovered using dynamic covalent chemistry'. Together they form a unique fingerprint.

    Cite this