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dc.contributor.authorMondal, Santanu
dc.contributor.authorGong, Xuefeng
dc.contributor.authorZhang, Xiaoqian
dc.contributor.authorSalinger, Ari J.
dc.contributor.authorZheng, Li
dc.contributor.authorSen, Sudeshna
dc.contributor.authorWeerapana, Eranthie
dc.contributor.authorZhang, Xuesen
dc.contributor.authorThompson, Paul R
dc.date2022-08-11T08:10:32.000
dc.date.accessioned2022-08-23T17:11:59Z
dc.date.available2022-08-23T17:11:59Z
dc.date.issued2019-07-05
dc.date.submitted2019-07-17
dc.identifier.citation<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. <a href="https://doi.org/10.1002/anie.201906334" target="_blank" title="Link to article on publisher's site">Link to article on publisher's website</a></p>
dc.identifier.issn1521-3773
dc.identifier.doi10.1002/anie.201906334
dc.identifier.pmid31276611
dc.identifier.urihttp://hdl.handle.net/20.500.14038/46408
dc.description.abstractProtein 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.
dc.language.isoen_US
dc.relation<p><a href="https://www.ncbi.nlm.nih.gov/pubmed/31276611" target="_blank" title="Link to article in PubMed">Link to article in PubMed</a></p>
dc.rights© 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.
dc.subjectActivity-based protein profiling
dc.subjectCovalent protein modification
dc.subjectHalogen Bonding
dc.subjectHistone citrullination
dc.subjectProtein arginine deiminase
dc.subjectBiochemical Phenomena, Metabolism, and Nutrition
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal and Pharmaceutical Chemistry
dc.subjectMedicinal Chemistry and Pharmaceutics
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.titleHalogen Bonding Increases the Potency and Isozyme-selectivity of Protein Arginine Deiminase 1 Inhibitors
dc.typeAccepted Manuscript
dc.source.journaltitleAngewandte Chemie (International ed. in English)
dc.source.volume58
dc.source.issue36
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1037&amp;context=publications&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/publications/18
dc.legacy.embargo2020-07-06T00:00:00-07:00
dc.identifier.contextkey14943026
dc.file.descriptionSupporting information
dc.file.descriptionFigure for Table of Contents
refterms.dateFOA2022-08-29T14:40:40Z
html.description.abstract<p>Protein 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.</p>
dc.identifier.submissionpathpublications/18
dc.contributor.departmentThompson Lab
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages12476-12480


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