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Bioorg Med Chem. 2014 Feb 15;22(4):1362-9. doi: 10.1016/j.bmc.2013.12.064. Epub 2014 Jan 8.

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

Author information

1
Department of Chemistry and The Kellogg School of Graduate Studies, The Scripps Research Institute-Florida, 130 Scripps Way, Jupiter, FL 33458, United States.
2
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.
3
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.

Abstract

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.

KEYWORDS:

7-Amino-quinoline-5,8-dione; Irreversible inhibitors; PADs; Protein arginine deiminase; Streptonigrin

PMID:
24440480
PMCID:
PMC3954981
DOI:
10.1016/j.bmc.2013.12.064
[Indexed for MEDLINE]
Free PMC Article

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