Author: ["Venugopal T. Bhat","Anne M. Caniard","Torsten Luksch","Ruth Brenk","Dominic J. Campopiano","Michael F. Greaney"]
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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. The composition of a dynamic combinatorial library can be altered by adding a target molecule that either stabilizes (or destabilizes) one or more of its members. The range of reversible chemical reactions compatible with biological targets such as proteins is somewhat limited, but now it has been shown that aniline-catalysed acylhydrazone formation is effective in this context. Cite this article
Bhat, V., Caniard, A., Luksch, T. et al. Nucleophilic catalysis of acylhydrazone equilibration for protein-directed dynamic covalent chemistry. Nature Chem 2, 490–497 (2010). https://doi.org/10.1038/nchem.658 