UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Program in Chemical Biology; Thompson Lab

Publication Date

2018-04-20

Document Type

Article Postprint

Disciplines

Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics

Abstract

Protein Arginine deiminases (PADs) play an important role in the pathogenesis of various diseases, including rheumatoid arthritis, multiple sclerosis, lupus, ulcerative colitis and breast cancer. Therefore, the development of PAD-inhibitors has drawn significant research interest in recent years. Herein, we describe the development of the first photoswitchable PAD-inhibitors. These compounds possess an azobenzene photoswitch to optically control PAD activity. Screening of a series of inhibitors structurally similar to BB-Cl-Amidine afforded compounds 1 and 2 as the most promising candidates for the light-controlled inhibition of PAD2; the cis-isomer of 1 is 10-fold more potent than its trans-isomer, whereas the trans-isomer of 2 is 45-fold more potent than the corresponding cis-isomer. The altered inhibitory potency upon photoisomerization has been confirmed in a competitive activity-based protein profiling (ABPP) assay. Further investigations indicate that the trans-isomer of 2 is an irreversible inhibitor, whereas the cis-isomer acts as a competitive inhibitor. In cells, the trans-isomer of compound 1 is completely inactive, whereas the cis-isomer inhibits histone H3-citrullination in a dose-dependent manner. Taken together, 1 serves as the foundation for developing photopharmaceuticals that can be activated at the desired tissue, using light, to treat diseases where PAD activity is dysregulated.

Keywords

protein arginine deiminases, photoswitch, photopharmaceuticals

Rights and Permissions

This document is the Accepted Manuscript version of a Published Work that will appear in final form in ACS Chemical Biology, copyright © American Chemical Society. To access the final edited and published work see https://doi.org/10.1021/acschembio.8b00053.

DOI of Published Version

10.1021/acschembio.8b00053

Source

ACS Chem Biol. 2018 Apr 20;13(4):1057-1065. doi: 10.1021/acschembio.8b00053. Epub 2018 Mar 16. Link to article on publisher's website

Journal/Book/Conference Title

ACS Chemical Biology

Related Resources

Link to article in PubMed

PubMed ID

29517899

Available for download on Saturday, April 20, 2019

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