Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation.
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Animals; Antineoplastic Agents; Cell Line; Cell Proliferation; Cell Survival; Enzyme Inhibitors; Humans; Hydrolases; Kinetics; Mice; Protein Binding; Protein Isoforms; Quinolines; Streptonigrin; Structure-Activity Relationship
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Protein citrullination is just one of more than 200 known PTMs. This modification, catalyzed by the protein arginine deiminases (PADs 1-4 and PAD6 in humans), converts the positively charged guanidinium group of an arginine residue into a neutral ureido-group. Given the strong links between dysregulated PAD activity and human disease, we initiated a program to develop PAD inhibitors as potential therapeutics for these and other diseases in which the PADs are thought to play a role. Streptonigrin which possesses both anti-tumor and anti-bacterial activity was later identified as a highly potent PAD4 inhibitor. In an effort to understand why streptonigrin is such a potent and selective PAD4 inhibitor, we explored its structure-activity relationships by examining the inhibitory effects of several analogues that mimic the A, B, C, and/or D rings of streptonigrin. We report the identification of the 7-amino-quinoline-5,8-dione core of streptonigrin as a highly potent pharmacophore that acts as a pan-PAD inhibitor.
Rights and Permissions
Citation: Bioorg Med Chem. 2014 Feb 15;22(4):1362-9. doi: 10.1016/j.bmc.2013.12.064. Epub 2014 Jan 8. Link to article on publisher's site
Dreyton, Christina J.; Anderson, Erin D.; Subramanian, Venkataraman; Boger, Dale L.; and Thompson, Paul R., "Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation." (2014). Thompson Lab Publications. 20.