title: A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, and in vitro and in vivo evaluation.
abstract: 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.
authors.affiliation: Department of Chemistry & Biochemistry, University of South Carolina, Columbia, 29208, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Luo
authors.forename: Bryan
authors.initials: B
authors.lastname: Knuckley
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stallcup
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases
chemical_list: D000081:Acetamides; D000578:Amidines; D004791:Enzyme Inhibitors; C509292:F-amidine; D006845:Hydrocarbons, Fluorinated; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases