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

Journal Publication ResearchOnline@JCU
Askin, Samuel;Bond, Thomas E.H.;Sorenson, Alanna E.;Moreau, Morgane J.J.;Antony, Helma;Davis, Rohan A.;Schaeffer, Patrick M.
Alanna SorensonPatrick Schaeffer
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.

Journal

Chemical Communications

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Volume

54

ISBN/ISSN

1364-548X

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Issue

14

Pages Count

4

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Publisher

Royal Society of Chemistry

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Date

N/A

EISSN

N/A

DOI

10.1039/c8cc00090e