Rebamipide and Derivatives are Potent, Selective Inhibitors of Histidine Phosphatase Activity of the Suppressor of T Cell Receptor Signaling Proteins
Rebamipide and Derivatives are Potent, Selective Inhibitors of Histidine Phosphatase Activity of the Suppressor of T Cell Receptor Signaling Proteins
复制标题
DOI：
10.1021/acs.jmedchem.3c01763
复制
发表时间：
2024-01-22
影响因子：
7.3
通讯作者：
French，Jarrod B.
中科院分区：
文献类型：
--
作者：
Aziz，Faisal;Reddy，Kanamata;French，Jarrod B.
T细胞受体信号（Sts）蛋白的抑制因子是免疫信号的负调节因子。这些蛋白质的基因失活导致对感染的显著抵抗。从590,000个化合物的高通量筛选中，我们确定了2-(1H)-喹诺啉酮衍生物利巴米胺，作为Sts磷酸酶活性的推定抑制剂。利巴米胺及其衍生物是具有竞争性的选择性Sts-1抑制剂，ic50值从低到亚微摩尔不等。SAR分析表明，喹啉酮，酸和酰胺部分都是活性所必需的。晶体结构证实了SAR，并揭示了这类化合物与蛋白质之间的关键相互作用。虽然利巴米胺具有较差的细胞渗透性，但我们证明了脂质体制剂可以灭活细胞中Sts-1的磷酸酶活性。这些研究表明Sts-1酶活性可以被药理学灭活，并为开发针对Sts蛋白的免疫增强疗法提供了基础工具和见解。
The suppressor of T cell receptor signaling (Sts) proteins are negative regulators of immune signaling. Genetic inactivation of these proteins leads to significant resistance to infection. From a 590,000 compound high-throughput screen, we identified the 2-(1H)-quinolinone derivative, rebamipide, as a putative inhibitor of Sts phosphatase activity. Rebamipide, and a small library of derivatives, are competitive, selective inhibitors of Sts-1 with IC50values from low to submicromolar. SAR analysis indicates that the quinolinone, the acid, and the amide moieties are all essential for activity. A crystal structure confirmed the SAR and reveals key interactions between this class of compound and the protein. Although rebamipide has poor cell permeability, we demonstrated that a liposomal preparation can inactivate the phosphatase activity of Sts-1 in cells. These studies demonstrate that Sts-1 enzyme activity can be pharmacologically inactivated and provide foundational tools and insights for the development of immune-enhancing therapies that target the Sts proteins.