Work

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

Year: 2006

Type: article

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.

Source: Journal of the American Chemical Society

DOI: 10.1021/ja0576233

Authors: Yuan Luo, Bryan Knuckley, Young-Ho Lee, Michael R. Stallcup, Paul R. Thompson

Institutions: University of Southern California, University of South Carolina

Language: English

Topic: Cancer-related gene regulation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funder: National Institute of Diabetes and Digestive and Kidney Diseases