Mondal, SantanuGong, XuefengZhang, XiaoqianSalinger, Ari J.Zheng, LiSen, SudeshnaWeerapana, EranthieZhang, XuesenThompson, Paul R2022-08-232022-08-232019-07-052019-07-17<p>Mondal S, Gong X, Zhang X, Salinger AJ, Zheng L, Sen S, Weerapana E, Zhang X, Thompson PR. Halogen Bonding Increases the Potency and Isozyme Selectivity of Protein Arginine Deiminase 1 Inhibitors. Angew Chem Int Ed Engl. 2019 Sep 2;58(36):12476-12480. doi: 10.1002/anie.201906334. Epub 2019 Jul 5. PMID: 31276611; PMCID: PMC6713606. </p>1521-377310.1002/anie.20190633431276611https://hdl.handle.net/20.500.14038/46408Protein Arginine Deiminases (PADs) hydrolyze the side chain of arginine to form citrulline. Aberrant PAD activity is associated with rheumatoid arthritis, multiple sclerosis, lupus, and certain cancers. These pathologies established the PADs as therapeutic targets and multiple PAD inhibitors are known. Herein, we describe the first highly potent PAD1-selective inhibitors (1 and 19). Detailed structure-activity relationships indicate that their potency and selectivity is due to the formation of a halogen bond with PAD1. Importantly, these inhibitors inhibit histone H3 citrullination in HEK293TPAD1 cells and mouse zygotes with excellent potency. Based on this scaffold, we also developed a PAD1-selective activity-based probe that shows remarkable cellular efficacy and proteome selectivity. Based on their potency and selectivity we expect that 1 and 19 will be widely used chemical tools to understand PAD1 biology.en-US© 2019 WILEY‐VCH Verlag GmbH. This is the peer reviewed version of the following article: Mondal, S. , Gong, X. , Zhang, X. , Salinger, A. ., Zheng, L. , Sen, S. , Weerapana, E. , Zhang, X. and Thompson, P. (2019), Halogen Bonding Increases the Potency and Isozyme‐selectivity of Protein Arginine Deiminase 1 Inhibitors. Angew. Chem. Int. Ed. doi:10.1002/anie.201906334, which has been published in final form at https://doi.org/10.1002/anie.201906334. First published 05 July 2019. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions, https://authorservices.wiley.com/author-resources/Journal-Authors/licensing/self-archiving.html.Activity-based protein profilingCovalent protein modificationHalogen BondingHistone citrullinationProtein arginine deiminaseBiochemistryEnzymes and CoenzymesAccepted Manuscripthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1037&amp;context=publications&amp;unstamped=1https://escholarship.umassmed.edu/publications/1814943026publications/18