Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism

Peptidyl arginine deiminases (PADs) are important enzymes in many diseases, especially those involving inflammation and autoimmunity. Despite many years of effort, developing isoform-specific inhibitors has been a challenge. We describe herein the discovery of a potent, noncovalent PAD2 inhibitor, w...

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Published in:ACS chemical biology 2024-10, Vol.19 (10), p.2186-2197
Main Authors: Byrnes, Laura J., Choi, Won Young, Balbo, Paul, Banker, Mary Ellen, Chang, Jeanne, Chen, Shi, Cheng, Xuemin, Cong, Yang, Culp, Jeff, Di, Hongxia, Griffor, Matt, Hall, Justin, Meng, Xiaoyun, Morgan, Barry, Mousseau, James J., Nicki, Jennifer, O’Connell, Thomas, Ramsey, Simeon, Shaginian, Alex, Shanker, Suman, Trujillo, John, Wan, Jinqiao, Vincent, Fabien, Wright, Stephen W., Vajdos, Felix
Format: Article
Language:English
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Summary:Peptidyl arginine deiminases (PADs) are important enzymes in many diseases, especially those involving inflammation and autoimmunity. Despite many years of effort, developing isoform-specific inhibitors has been a challenge. We describe herein the discovery of a potent, noncovalent PAD2 inhibitor, with selectivity over PAD3 and PAD4, from a DNA-encoded library. The biochemical and biophysical characterization of this inhibitor and two noninhibitory binders indicated a novel, Ca2+ competitive mechanism of inhibition. This was confirmed via X-ray crystallographic analysis. Finally, we demonstrate that this inhibitor selectively inhibits PAD2 in a cellular context.
ISSN:1554-8929
1554-8937
1554-8937
DOI:10.1021/acschembio.4c00397