Mie Yasuhiro, Mikami Chitose, Yasutake Yoshiaki, Shigemura Yuki, Yamashita Taku, Tsujino Hirofumi
Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan.
Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), AIST, Tokyo 169-8555, Japan.
Pharmaceuticals (Basel). 2025 Feb 28;18(3):352. doi: 10.3390/ph18030352.
An accurate and rapid analysis of human indoleamine 2,3-dioxygenase (hIDO) is crucial for the development of anticancer pharmaceuticals because of the role of hIDO in promoting tumoral immune escape. However, the conventional assay of hIDO is limited by interference from reductants, which are used to reduce the heme iron to begin the hIDO catalytic reaction. A direct electrochemical method was applied to drive the hIDO reaction. The nanostructured gold electrode enabled the electrochemical reduction of the heme iron of hIDO1. In the presence of substrates (tryptophan and oxygen), a bioelectrocatalytic current was observed, confirming an electrochemically driven hIDO reaction. A well-known inhibitor of hIDO, epacadostat, hindered this catalytic signal according to its concentration, demonstrating the rapid evaluation of its inhibition activity for the hIDO reaction. Through an in silico study using the proposed electrochemical assay system, we discovered a strong inhibitor candidate with a half-maximal inhibitory concentration of 10 nM. An accurate and rapid assay system in drug discovery for hIDO and kynureine pathway-targeted immunotherapy has been developed.
由于人吲哚胺2,3-双加氧酶（hIDO）在促进肿瘤免疫逃逸中所起的作用，对其进行准确快速的分析对于抗癌药物的开发至关重要。然而，传统的hIDO检测方法受到还原剂干扰的限制，还原剂用于将血红素铁还原以启动hIDO催化反应。应用了一种直接电化学方法来驱动hIDO反应。纳米结构金电极能够实现hIDO1血红素铁的电化学还原。在底物（色氨酸和氧气）存在的情况下，观察到生物电催化电流，证实了电化学驱动的hIDO反应。一种著名的hIDO抑制剂依帕司他，根据其浓度阻碍了这种催化信号，证明了对其对hIDO反应抑制活性的快速评估。通过使用所提出的电化学检测系统进行计算机模拟研究，我们发现了一种半最大抑制浓度为10 nM的强抑制剂候选物。已经开发出一种用于hIDO和犬尿氨酸途径靶向免疫治疗药物发现的准确快速检测系统。
