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Issue 14, 2018
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Selective protein unfolding: a universal mechanism of action for the development of irreversible inhibitors

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Abstract

High-throughput differential scanning fluorimetry of GFP-tagged proteins (HT-DSF-GTP) was applied for the identification of novel enzyme inhibitors acting by a mechanism termed: selective protein unfolding (SPU). Four different protein targets were interrogated with the same library to identify target-selective hits. Several hits selectively destabilized bacterial biotin protein ligase. Structure–activity relationship data confirmed a structure-dependent mechanism of protein unfolding. Simvastatin and altenusin were confirmed to irreversibly inactivate biotin protein ligase. The principle of SPU combined with HT-DSF-GTP affords an invaluable and innovative workflow for the identification of new inhibitors with potential applications as antimicrobials and other biocides.

Graphical abstract: Selective protein unfolding: a universal mechanism of action for the development of irreversible inhibitors

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Publication details

The article was received on 05 Jan 2018, accepted on 20 Jan 2018 and first published on 22 Jan 2018


Article type: Communication
DOI: 10.1039/C8CC00090E
Citation: Chem. Commun., 2018,54, 1738-1741
  • Open access: Creative Commons BY-NC license
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    Selective protein unfolding: a universal mechanism of action for the development of irreversible inhibitors

    S. Askin, T. E. H. Bond, A. E. Sorenson, M. J. J. Moreau, H. Antony, R. A. Davis and P. M. Schaeffer, Chem. Commun., 2018, 54, 1738
    DOI: 10.1039/C8CC00090E

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