Nucleophilic catalysis of acylhydrazone equilibration for protein-directed dynamic covalent chemistry

Research output: Contribution to journalArticle

  • External authors:
  • Venugopal T. Bhat
  • Anne M. Caniard
  • Torsten Luksch
  • Ruth Brenk
  • Dominic J. Campopiano

Abstract

Dynamic covalent chemistry uses reversible chemical reactions to set up an equilibrating network of molecules at thermodynamic equilibrium, which can adjust its composition in response to any agent capable of altering the free energy of the system. When the target is a biological macromolecule, such as a protein, the process corresponds to the protein directing the synthesis of its own best ligand. Here, we demonstrate that reversible acylhydrazone formation is an effective chemistry for biological dynamic combinatorial library formation. In the presence of aniline as a nucleophilic catalyst, dynamic combinatorial libraries equilibrate rapidly at pH 6.2, are fully reversible, and may be switched on or off by means of a change in pH. We have interfaced these hydrazone dynamic combinatorial libraries with two isozymes from the glutathione S-transferase class of enzyme, and observed divergent amplification effects, where each protein selects the best-fitting hydrazone for the hydrophobic region of its active site. © 2010 Macmillan Publishers Limited. All rights reserved.

Bibliographical metadata

Original languageEnglish
Pages (from-to)490-497
Number of pages7
JournalNature Chemistry
Volume2
Issue number6
DOIs
StatePublished - Jun 2010