UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Thompson Lab

Publication Date

2019-07-05

Document Type

Article Postprint

Disciplines

Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Enzymes and Coenzymes | Medicinal and Pharmaceutical Chemistry | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry

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.

Keywords

Activity-based protein profiling, Covalent protein modification, Halogen Bonding, Histone citrullination, Protein arginine deiminase

Rights and Permissions

© 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. 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.

DOI of Published Version

10.1002/anie.201906334

Source

Angew Chem Int Ed Engl. 2019 Jul 5. doi: 10.1002/anie.201906334. [Epub ahead of print]. Link to article on publisher's website

Journal/Book/Conference Title

Angewandte Chemie (International ed. in English)

Related Resources

Link to article in PubMed

PubMed ID

31276611

Available for download on Monday, July 06, 2020

Share

COinS