A fluoroacetamidine-based inactivator of protein arginine deiminase 4: Design, synthesis, and in vitro and in vivo evaluation
A fluoroacetamidine-based inactivator of protein arginine deiminase 4: Design, synthesis, and in vitro and in vivo evaluation
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DOI：
10.1021/ja0576233
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发表时间：
2006-02-01
影响因子：
15
通讯作者：
Thompson, PR
中科院分区：
文献类型：
--
作者：
Luo, Y;Knuckley, B;Thompson, PR
蛋白精氨酸脱亚胺酶 4 (PAD4) 是一种钙依赖性转录辅阻遏物，与类风湿性关节炎的发病和进展有关。在此，我们描述了含氟乙脒的化合物 N-α-苯甲酰基-N5-(2-氟-1-亚氨基乙基)-l-鸟氨酸酰胺1（以下简称 F-脒）的合成和体外评价，它是迄今为止描述的最有效的 PAD4 抑制剂。本文描述的其他研究表明 F-脒还可以抑制体内 PAD4 活性。该化合物的生物利用度表明 F-脒将成为 PAD4 功能的强大化学探针，可用于剖析该酶在类风湿性关节炎和转录控制中的作用。抑制具有不可逆性这一事实表明，通过适当的功能化，F-脒类似物将成为稳健的基于活性的蛋白质分析和蛋白质组捕获试剂。
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-α-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.