Photochemical Control of Protein Arginine Deiminase (PAD) Activity.

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.

• Authors: Santanu Mondal, Sangram S Parelkar, Mitesh Nagar, Paul R Thompson
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 13 Issue 4 Pg. 1057-1065 (04 20 2018) ISSN: 1554-8937 [Electronic] United States
• PMID: 29517899 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Azo Compounds
• Enzyme Inhibitors
• N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide
• Ornithine
• Hydrolases
• PADI2 protein, human
• Protein-Arginine Deiminase Type 1
• Protein-Arginine Deiminase Type 2
• Protein-Arginine Deiminases
• azobenzene

Topics

• Azo Compounds
• Enzyme Inhibitors (pharmacology)
• Humans
• Hydrolases
• Isomerism
• Ornithine (analogs & derivatives)
• Photochemical Processes
• Protein-Arginine Deiminase Type 1
• Protein-Arginine Deiminase Type 2
• Protein-Arginine Deiminases (antagonists & inhibitors, metabolism)