Department of Biochemistry and Molecular Pharmacology; Program in Chemical Biology; Thompson Lab
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
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.
protein arginine deiminases, photoswitch, photopharmaceuticals
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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
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
ACS Chemical Biology
Mondal S, Parelkar SS, Nagar M, Thompson PR. (2018). Photochemical Control of Protein Arginine Deiminase (PAD) Activity. Thompson Lab Publications. https://doi.org/10.1021/acschembio.8b00053. Retrieved from https://escholarship.umassmed.edu/thompson/116