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    Halogen Bonding Increases the Potency and Isozyme-selectivity of Protein Arginine Deiminase 1 Inhibitors

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    Authors
    Mondal, Santanu
    Gong, Xuefeng
    Zhang, Xiaoqian
    Salinger, Ari J.
    Zheng, Li
    Sen, Sudeshna
    Weerapana, Eranthie
    Zhang, Xuesen
    Thompson, Paul R
    UMass Chan Affiliations
    Thompson Lab
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Accepted Manuscript
    Publication Date
    2019-07-05
    Keywords
    Activity-based protein profiling
    Covalent protein modification
    Halogen Bonding
    Histone citrullination
    Protein arginine deiminase
    Biochemical Phenomena, Metabolism, and Nutrition
    Biochemistry
    Enzymes and Coenzymes
    Medicinal and Pharmaceutical Chemistry
    Medicinal Chemistry and Pharmaceutics
    Medicinal-Pharmaceutical Chemistry
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    Abstract
    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.
    Source

    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. Link to article on publisher's website

    DOI
    10.1002/anie.201906334
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/46408
    PubMed ID
    31276611
    Related Resources

    Link to article in PubMed

    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.
    ae974a485f413a2113503eed53cd6c53
    10.1002/anie.201906334
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