N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Amidines; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Autoantibodies; Citrulline; Collagen Type II; Enzyme Inhibitors; Hydrolases; Immunosuppressive Agents; Male; Mice; Mice, Inbred DBA; Ornithine; Peptides, Cyclic; Severity of Illness Index; Synovial Membrane
Biochemistry | Enzymes and Coenzymes | Immunology and Infectious Disease | Medicinal-Pharmaceutical Chemistry | Musculoskeletal Diseases | Rheumatology | Therapeutics
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-alpha-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 approximately 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.
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Citation: J Immunol. 2011 Apr 1;186(7):4396-404. doi: 10.4049/jimmunol.1001620. Link to article on publisher's site. Epub 2011 Feb 23.
Willis, Van C.; Thompson, Paul R.; and Holers, V. Michael, "N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis" (2011). Thompson Lab Publications. 53.