Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation.
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Authors
Dreyton, Christina J.Anderson, Erin D.
Subramanian, Venkataraman
Boger, Dale L.
Thompson, Paul R
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2014-02-15Keywords
AnimalsAntineoplastic 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
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Show full item recordAbstract
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.Source
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 siteDOI
10.1016/j.bmc.2013.12.064Permanent Link to this Item
http://hdl.handle.net/20.500.14038/50009Notes
At the time of publication, Christina Dreyton and Paul Thompson were not yet affiliated with UMass Medical School.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.bmc.2013.12.064