Inhibitors and inactivators of protein arginine deiminase 4: Functional and structural characterization
Inhibitors and inactivators of protein arginine deiminase 4: Functional and structural characterization
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DOI：
10.1021/bi061180d
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发表时间：
2006-10-03
期刊：
影响因子：
2.9
通讯作者：
Thompson, Paul R.
中科院分区：
文献类型：
--
作者：
Luo, Yuan;Arita, Kyouhei;Thompson, Paul R.
蛋白质精氨酸脱亚氨酶4（PAD4）是一种转录共调节因子，可催化蛋白质中特定精氨酸残基在钙依赖的情况下转化为瓜氨酸。最近，我们报道了F - 脒的合成与特性，F - 脒是一种高效且具有生物可利用性的PAD4不可逆失活剂。在此，我们阐述了确定F - 脒诱导PAD4失活所需的空间位阻和离去基团的研究工作、PAD4 - F - 脒与钙形成的复合物的结构，以及使用N - α - 苯甲酰基 - N - 5 -（2 - 氯 - 1 - 亚氨基乙基） - L - 鸟氨酸酰胺（Cl - 脒）进行的体内研究，Cl - 脒是一种效力增强的PAD4失活剂。本文所述的PAD4失活剂将成为有用的药理学探针，用于阐释该酶尚未完全明确的生理作用。此外，它们有望成为治疗类风湿性关节炎的先导化合物，因为越来越多的证据表明PAD4在这种慢性自身免疫性疾病的发病和进展中发挥作用。
Protein arginine deiminase 4 (PAD4) is a transcriptional coregulator that catalyzes the calcium-dependent conversion of specific arginine residues in proteins to citrulline. Recently, we reported the synthesis and characterization of F-amidine, a potent and bioavailable irreversible inactivator of PAD4. Herein, we report our efforts to identify the steric and leaving group requirements for F-amidine-induced PAD4 inactivation, the structure of the PAD4-F-amidine, calcium complex, and in vivo studies with N-alpha-benzoyl-N-5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine), a PAD4 inactivator with enhanced potency. The PAD4 inactivators described herein will be useful pharmacological probes in characterizing the incompletely defined physiological role(s) of this enzyme. In addition, they represent potential lead compounds for the treatment of rheumatoid arthritis because a growing body of evidence supports a role for PAD4 in the onset and progression of this chronic autoimmune disorder.