title: N-α-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis.
abstract: Rheumatoid arthritis is associated with the development of autoantibodies to citrullinated self-proteins. Citrullinated synovial proteins, which are generated via the actions of the protein arginine deiminases (PADs), are known to develop in the murine collagen-induced arthritis (CIA) model of inflammatory arthritis. Given these findings, we evaluated whether N-α-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine), a recently described pan-PAD inhibitor, could affect the development of arthritis and autoimmunity by treating mice in the CIA model with Cl-amidine on days 0-35. Cl-amidine treatment reduced total synovial and serum citrullination, decreased clinical disease activity by ∼50%, and significantly decreased IgG2a anti-mouse type II collagen Abs. Additionally, histopathology scores and total complement C3 deposition were significantly lower in Cl-amidine-treated mice compared with vehicle controls. Synovial microarray analyses demonstrated decreased IgG reactivity to several native and citrullinated epitopes compared with vehicle controls. Cl-amidine treatment had no ameliorative effect on collagen Ab-induced arthritis, suggesting its primary protective mechanism was not mediated through effector pathways. Reduced levels of citrullinated synovial proteins observed in mice treated with Cl-amidine are consistent with the notion that Cl-amidine derives its efficacy from its ability to inhibit the deiminating activity of PADs. In total, these results suggested that PADs are necessary participants in the autoimmune and subsequent inflammatory processes in CIA. Cl-amidine may represent a novel class of disease-modifying agents that modulate aberrant citrullination, and perhaps other immune processes, necessary for the development of inflammatory arthritis.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Van C
authors.initials: VC
authors.lastname: Willis
authors.forename: Alison M
authors.initials: AM
authors.lastname: Gizinski
authors.forename: Nirmal K
authors.initials: NK
authors.lastname: Banda
authors.forename: Corey P
authors.initials: CP
authors.lastname: Causey
authors.forename: Bryan
authors.initials: B
authors.lastname: Knuckley
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Cordova
authors.forename: Yuan
authors.initials: Y
authors.lastname: Luo
authors.forename: Brandt
authors.initials: B
authors.lastname: Levitt
authors.forename: Magdalena
authors.initials: M
authors.lastname: Glogowska
authors.forename: Piyanka
authors.initials: P
authors.lastname: Chandra
authors.forename: Liudmila
authors.initials: L
authors.lastname: Kulik
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
authors.forename: William P
authors.initials: WP
authors.lastname: Arend
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
mesh_terms: D000578:Amidines / Q000627:therapeutic use*; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis / Q000633:toxicity; D002956:Citrulline / Q000378:metabolism; D024043:Collagen Type II / Q000037:antagonists & inhibitors / Q000276:immunology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009952:Ornithine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000276:immunology / Q000378:metabolism; D000076342:Protein-Arginine Deiminases; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000578:Amidines; D001323:Autoantibodies; D024043:Collagen Type II; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; C558727:N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D002956:Citrulline; D009952:Ornithine; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases