A Fluoroacetamidine-Based Inactivator of Protein Arginine Deiminase 4: Design, Synthesis, and in Vitro and in Vivo Evaluation

J. Am. Chem. Soc., 128 (4), 1092 -1093, 2006. 10.1021/ja0576233 S0002-7863(05)07623-7
Web Release Date: January 7, 2006

A Fluoroacetamidine-Based Inactivator of Protein Arginine Deiminase 4: Design, Synthesis, and in Vitro and in Vivo Evaluation

Yuan Luo, Bryan Knuckley, Young-Ho Lee, Michael R. Stallcup, and Paul R. Thompson*

Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, and Department of Biochemistry & Molecular Biology, University of Southern California, 1333 San Pablo Street, MCA 51A, Los Angeles, California 90089

thompson@mail.sc.edu

Received November 8, 2005

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--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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