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

Venugopal T. Bhat, Anne M. Caniard, Torsten Luksch, Ruth Brenk, Dominic J. Campopiano, Michael F. Greaney

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    123 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)490-497
    Number of pages8
    JournalNature Chemistry
    Volume2
    Issue number6
    DOIs
    Publication statusPublished - Jun 2010

    Keywords

    • GLUTATHIONE-S-TRANSFERASE
    • VIRTUAL COMBINATORIAL LIBRARIES
    • SCHISTOSOMA-JAPONICUM
    • CHEMICAL EVOLUTION
    • SYSTEMS CHEMISTRY
    • DRUG DISCOVERY
    • INHIBITORS
    • AMPLIFICATION
    • RECEPTOR
    • RECOGNITION

    Cite this

    Bhat, V. T., Caniard, A. M., Luksch, T., Brenk, R., Campopiano, D. J., & Greaney, M. F. (2010). Nucleophilic catalysis of acylhydrazone equilibration for protein-directed dynamic covalent chemistry. Nature Chemistry, 2(6), 490-497. https://doi.org/10.1038/NCHEM.658