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

Askin, Samuel, Bond, Thomas E.H., Sorenson, Alanna E., Moreau, Morgane J.J., Antony, Helma, Davis, Rohan A., and Schaeffer, Patrick M. (2018) Selective protein unfolding: a universal mechanism of action for the development of irreversible inhibitors. Chemical Communications, 54 (14). pp. 1738-1741.

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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.

Item ID: 52355
Item Type: Article (Research - C1)
ISSN: 1364-548X
Additional Information:

This article is licensed under a Creative Commons Attribution-Non Commercial 3.;0 Unported Licence.

Date Deposited: 29 Mar 2018 05:36
FoR Codes: 03 CHEMICAL SCIENCES > 0304 Medicinal and Biomolecular Chemistry > 030499 Medicinal and Biomolecular Chemistry not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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