Title

Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor.

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Date

6-1-2011

Document Type

Article

Medical Subject Headings

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

Disciplines

Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics

Abstract

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.

Rights and Permissions

Citation: 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

Comments

At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

Related Resources

Link to Article in PubMed