A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, and in vitro and in vivo evaluation
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Acetamides; Amidines; Animals; Drug Design; Enzyme Activation; Enzyme Inhibitors; Hydrocarbons, Fluorinated; Hydrolases; Kinetics
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Protein arginine deiminase 4 (PAD4) is a calcium-dependent transcriptional corepressor that has been implicated in the onset and progression of rheumatoid arthritis. Herein we describe the synthesis and in vitro evaluation of a fluoroacetamidine-containing compound, N-alpha-benzoyl-N5-(2-fluoro-1-iminoethyl)-l-ornithine amide, 1, hereafter referred to as F-amidine, that is the most potent PAD4 inhibitor ever described. Additional studies described herein indicate that F-amidine can also inhibit PAD4 activity in vivo. The bioavailability of this compound suggests that F-amidine will be a powerful chemical probe of PAD4 function that can be used to dissect the roles of this enzyme in both rheumatoid arthritis and transcriptional control. The fact that inhibition is of an irreversible nature suggests that, with appropriate functionalization, F-amidine analogues will be robust activity-based protein-profiling and proteomic capture reagents.
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Citation: J Am Chem Soc. 2006 Feb 1;128(4):1092-3. Link to article on publisher's site
Luo, Yuan; Knuckley, Bryan; Lee, Young-Ho; Stallcup, Michael R.; and Thompson, Paul R., "A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, and in vitro and in vivo evaluation" (2006). Thompson Lab Publications. 80.