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 AA, Causey CP, Knuckley B, Jones JE, Poudyal D, Davis T, Chumanevich AP, Matesic LE, Thompson PR, Hofseth LJ. (2011). Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor.. Thompson Lab Publications. https://doi.org/10.1152/ajpgi.00435.2010. Retrieved from https://escholarship.umassmed.edu/thompson/47