Bivalent Enzyme Inhibitors Discovered Using Dynamic Covalent Chemistry | Zendy

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

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Bivalent Enzyme Inhibitors Discovered Using Dynamic Covalent Chemistry

Author(s) -

Clipson Alexandra J.,

Bhat Venugopal T.,

McNae Iain,

Caniard Anne M.,

Campopiano Dominic J.,

Greaney Michael F.

Publication year - 2012

Publication title -

chemistry – a european journal

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.687

H-Index - 242

eISSN - 1521-3765

pISSN - 0947-6539

DOI - 10.1002/chem.201201507

Subject(s) - chemistry , covalent bond , bivalent (engine) , conjugated system , glutathione , enzyme , stereochemistry , combinatorial chemistry , isozyme , biochemistry , organic chemistry , polymer , metal

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 ( K i =61 n M for mGSTM1‐1) and demonstrates that DCC can be used to simultaneously interrogate binding sites on different subunits of a dimeric protein.

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