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

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.

• Authors: Christina J Dreyton, Erin D Anderson, Venkataraman Subramanian, Dale L Boger, Paul R Thompson
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 4 Pg. 1362-9 (Feb 15 2014) ISSN: 1464-3391 [Electronic] England
• PMID: 24440480 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Protein Isoforms
• Quinolines
• Streptonigrin
• quinoline
• Hydrolases
• Protein-Arginine Deiminases

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Cell Line
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Enzyme Inhibitors (chemistry, metabolism, pharmacology)
• Humans
• Hydrolases (antagonists & inhibitors, metabolism)
• Kinetics
• Mice
• Protein Binding
• Protein Isoforms (antagonists & inhibitors, metabolism)
• Protein-Arginine Deiminases
• Quinolines (chemistry)
• Streptonigrin (chemistry, metabolism, pharmacology)
• Structure-Activity Relationship