Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation.
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.
Department of Chemistry and The Kellogg School of Graduate Studies, The Scripps Research Institute-Florida, 130 Scripps Way, Jupiter, FL 33458, United States.
Christina J
CJ
Dreyton
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States.
Erin D
ED
Anderson
Department of Chemistry and The Kellogg School of Graduate Studies, The Scripps Research Institute-Florida, 130 Scripps Way, Jupiter, FL 33458, United States.
Venkataraman
V
Subramanian
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States.
Dale L
DL
Boger
Department of Chemistry and The Kellogg School of Graduate Studies, The Scripps Research Institute-Florida, 130 Scripps Way, Jupiter, FL 33458, United States. Electronic address: pthompso@scripps.edu.
Paul R
PR
Thompson
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D000076342:Protein-Arginine Deiminases; D011804:Quinolines / Q000737:chemistry; D013308:Streptonigrin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D011804:Quinolines; D013308:Streptonigrin; C037219:quinoline; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases
7-Amino-quinoline-5,8-dione; Irreversible inhibitors; PADs; Protein arginine deiminase; Streptonigrin