Kunieda Kazuki, Yamauchi Hiromasa, Kawaguchi Mitsuyasu, Ieda Naoya, Nakagawa Hidehiko
Graduate School of Pharmaceutical Science, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi, Japan.
Graduate School of Pharmaceutical Science, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi, Japan.
Bioorg Med Chem Lett. 2018 Mar 1;28(5):969-973. doi: 10.1016/j.bmcl.2018.01.026. Epub 2018 Feb 10.
Peptidyl arginine deiminases (PADs) catalyze the post-translational deimination of peptidyl arginine residues to form citrulline residues. Aberrant citrullination of histones by one of the PAD isozymes, PAD4, is associated with various diseases, including rheumatoid arthritis, so high-throughput screening systems are needed to identify PAD4 inhibitors as chemical tools to investigate the role of PAD4, and as candidate therapeutic agents. Here, we utilized the addition-cyclization reaction between phenylglyoxal and citrulline under acidic conditions to design turn-on fluorescent probes for citrulline based on the donor-excited photoinduced electron transfer (d-PeT) mechanism. Among several derivatives of phenylglyoxal bearing a fluorescent moiety, we found that FGME enabled detection of citrulline without a neutralization process, and we used it to establish a simple methodology for turn-on fluorescence detection of citrulline.
肽基精氨酸脱亚氨酶（PADs）催化肽基精氨酸残基的翻译后脱亚氨基作用，形成瓜氨酸残基。PAD同工酶之一PAD4对组蛋白的异常瓜氨酸化与包括类风湿性关节炎在内的多种疾病相关，因此需要高通量筛选系统来鉴定PAD4抑制剂，将其作为研究PAD4作用的化学工具以及候选治疗药物。在此，我们利用苯乙二醛和瓜氨酸在酸性条件下的加成环化反应，基于供体激发光诱导电子转移（d-PeT）机制设计了用于瓜氨酸的开启型荧光探针。在几种带有荧光基团的苯乙二醛衍生物中，我们发现FGME无需中和过程就能检测瓜氨酸，并且我们用它建立了一种用于瓜氨酸开启型荧光检测的简单方法。
