Discovery of Novel Potential Reversible Peptidyl Arginine Deiminase Inhibitor
Discovery of Novel Potential Reversible Peptidyl Arginine Deiminase Inhibitor
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DOI：
10.3390/ijms20092174
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发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Mydel, Piotr
中科院分区：
文献类型：
--
作者：
Aliko, Ardita;Kaminska, Marta;Mydel, Piotr
瓜氨酸化是一种翻译后修饰，由肽精氨酸脱亚胺酶（pad）催化，pad是一种独特的酶家族，可将肽精氨酸转化为肽基瓜氨酸。在类风湿性关节炎（RA）、阿尔茨海默病、多发性硬化症和癌症中观察到过表达和/或增加的PAD活性。此外，细菌性PAD，如牙龈卟啉单胞菌PAD (PPAD)，可能在RA的发病机制中起作用，表明PAD是有希望的治疗靶点。本文研究了6种新化合物作为人类PAD4和PPAD的潜在抑制剂，并与不可逆的PAD抑制剂cl -脒进行了比较。其中四种化合物（化合物2、3、4和6）在体外实验中对PAD4具有微摩尔范围的抑制作用，而对PPAD没有作用。化合物4对pad4诱导的H3组蛋白瓜氨酸化的抑制作用优于氨基氯。综上所述，化合物4具有很高的疗效，为寻找新的RA治疗策略提供了一个有希望的方向。
Citrullination, a posttranslational modification, is catalyzed by peptidylarginine deiminases (PADs), a unique family of enzymes that converts peptidyl-arginine to peptidyl-citrulline. Overexpression and/or increased PAD activity is observed in rheumatoid arthritis (RA), Alzheimer's disease, multiple sclerosis, and cancer. Moreover, bacterial PADs, such as Porphyromonas gingivalis PAD (PPAD), may have a role in the pathogenesis of RA, indicating PADs as promising therapeutic targets. Herein, six novel compounds were examined as potential inhibitors of human PAD4 and PPAD, and compared to an irreversible PAD inhibitor, Cl-amidine. Four of the tested compounds (compounds 2, 3, 4, and 6) exhibited a micromolar-range inhibition potency against PAD4 and no effect against PPAD in the in vitro assays. Compound 4 was able to inhibit the PAD4-induced citrullination of H3 histone with higher efficiency than Cl-amidine. In conclusion, compound 4 was highly effective and presents a promising direction in the search for novel RA treatment strategies.