Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation

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• 作者：Christina J. Dreyton ; Erin D. Anderson ; Venkataraman Subramanian ; Dale L. Boger ; Paul R. Thompson
• 关键词：PADs ; Streptonigrin ; 7-Amino-quinoline-5 ; 8-dione ; Protein arginine deiminase ; Irreversible inhibitors
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：15 February, 2014
• 年：2014
• 卷：22
• 期：4
• 页码：1362-1369
• 全文大小：681 K

文摘

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.