Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor.
Department of Biochemistry and Molecular Pharmacology
Administration, Oral; Animals; Anti-Inflammatory Agents; Apoptosis; Arginine; Citrulline; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gastrointestinal Agents; HT29 Cells; Humans; Hydrolases; Mice; Mice, Inbred C57BL; Ornithine; Protein Processing, Post-Translational; Up-Regulation
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Inflammatory bowel diseases (IBDs), mainly Crohn's disease and ulcerative colitis, are dynamic, chronic inflammatory conditions that are associated with an increased colon cancer risk. Inflammatory cell apoptosis is a key mechanism for regulating IBD. Peptidylarginine deiminases (PADs) catalyze the posttranslational conversion of peptidylarginine to peptidylcitrulline in a calcium-dependent, irreversible reaction and mediate the effects of proinflammatory cytokines. Because PAD levels are elevated in mouse and human colitis, we hypothesized that a novel small-molecule inhibitor of the PADs, i.e., chloramidine (Cl-amidine), could suppress colitis in a dextran sulfate sodium mouse model. Results are consistent with this hypothesis, as demonstrated by the finding that Cl-amidine treatment, both prophylactic and after the onset of disease, reduced the clinical signs and symptoms of colitis, without any indication of toxic side effects. Interestingly, Cl-amidine drives apoptosis of inflammatory cells in vitro and in vivo, providing a mechanism by which Cl-amidine suppresses colitis. In total, these data help validate the PADs as therapeutic targets for the treatment of IBD and further suggest Cl-amidine as a candidate therapy for this disease.
DOI of Published Version
Am J Physiol Gastrointest Liver Physiol. 2011 Jun;300(6):G929-38. doi: 10.1152/ajpgi.00435.2010. Epub 2011 Mar 17. Link to article on publisher's site
American journal of physiology. Gastrointestinal and liver physiology
Chumanevich, Alexander A.; Causey, Corey P.; Knuckley, Bryan; Jones, Justin E.; Poudyal, Deepak; Davis, Tia; Chumanevich, Alena P.; Matesic, Lydia E.; Thompson, Paul R.; and Hofseth, Lorne J., "Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor." (2011). Thompson Lab Publications. 47.