Discovery and Mechanistic Study of a Class of Protein Arginine Methylation Inhibitors
Discovery and Mechanistic Study of a Class of Protein Arginine Methylation Inhibitors
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DOI：
10.1021/jm100416n
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发表时间：
2010-08-26
影响因子：
7.3
通讯作者：
Zheng, Yujun George
中科院分区：
文献类型：
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作者：
Feng, You;Li, Mingyong;Zheng, Yujun George
蛋白质精氨酸甲基化调节多种生物学过程，如染色质重塑和RNA剪接。蛋白质精氨酸甲基转移酶（PRMTs）的功能障碍与许多人类疾病有关。因此，蛋白质精氨酸甲基化的小分子抑制剂具有巨大的治疗开发潜力。在此，我们报告了一种通过独特机制以微摩尔效力阻断PRMT 1介导的精氨酸甲基化的化合物。大多数发现的化合物带有萘和磺酸盐基团，并且在结构上不同于典型的PRMT底物，例如，组蛋白H4和富含甘氨酸和甘氨酸的序列。为了阐明抑制的分子基础，我们进行了各种动力学和生物物理测定。合并的数据表明，这种类型的萘基-磺基（NS）分子直接靶向底物，而不是PRMT所观察到的抑制。我们还发现苏拉明有效地抑制PRMT 1活性。这些新的PRMT抑制剂的发现及其独特的抑制机制为蛋白质精氨酸甲基化的化学调控提供了新的途径。
Protein arginine methylation regulates multiple biological processes such as chromatin remodeling and RNA splicing. Malfunction of protein arginine methyltransferases (PRMTs) is correlated with many human diseases. Thus, small molecule inhibitors of protein arginine methylation are of great potential for therapeutic development. Herein, we report a type of compound that blocks PRMT1-mediated arginine methylation at micromolar potency through a unique mechanism. Most of the discovered compounds bear naphthalene and sulfonate groups and are structurally different from typical PRMT substrates, for example, histone H4 and glycine- and arginine-rich sequences. To elucidate the molecular basis of inhibition, we conducted a variety of kinetic and biophysical assays. The combined data reveal that this type of naphthyl-sulfo (NS) molecule directly targets the substrates but not PRMTs for the observed inhibition. We also found that suramin effectively inhibited PRMT1 activity. These findings about novel PRMT inhibitors and their unique inhibition mechanism provide a new way for chemical regulation of protein arginine methylation.