title: Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor.
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.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, 29208, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Chumanevich
authors.forename: Corey P
authors.initials: CP
authors.lastname: Causey
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Knuckley
authors.forename: Justin E
authors.initials: JE
authors.lastname: Jones
authors.forename: Deepak
authors.initials: D
authors.lastname: Poudyal
authors.forename: Alena P
authors.initials: AP
authors.lastname: Chumanevich
authors.forename: Tia
authors.initials: T
authors.lastname: Davis
authors.forename: Lydia E
authors.initials: LE
authors.lastname: Matesic
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.forename: Lorne J
authors.initials: LJ
authors.lastname: Hofseth
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D019073:HT29 Cells; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000076342:Protein-Arginine Deiminases; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; C558727:N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide; D002956:Citrulline; D016264:Dextran Sulfate; D001120:Arginine; D009952:Ornithine; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases