A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, and in vitro and in vivo evaluation

摘要: 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 synthesis vitro evaluation fluoroacetamidine-containing compound, N-α-benzoyl-N5-(2-fluoro-1-iminoethyl)-l-ornithine amide, 1, hereafter referred to as F-amidine, most potent PAD4 inhibitor ever described. Additional studies described herein indicate F-amidine can also inhibit activity vivo. The bioavailability this compound suggests will be powerful chemical probe function used dissect roles enzyme both arthritis control. fact inhibition an irreversible nature that, with appropriate functionalization, analogues robust activity-based protein-profiling proteomic capture reagents.