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

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Animals; Antineoplastic 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


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.

DOI of Published Version



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 site

Journal/Book/Conference Title

Bioorganic and medicinal chemistry


At the time of publication, Christina Dreyton and Paul Thompson were not yet affiliated with UMass Medical School.

Related Resources

Link to Article in PubMed