Blevins Derek J, Hanley Ronan, Bolduc Trevor, Powell David A, Gignac Michael, Walker Kayleigh, Carr Mark D, Hof Fraser, Wulff Jeremy E
Department of Chemistry, University of Victoria, PO Box 3065 STN CSC, Victoria, British Columbia V8W 3V6, Canada.
Inception Sciences Canada, 210-887 Great Northern Way, Vancouver, British Columbia V5T 4T5, Canada.
ACS Med Chem Lett. 2019 Jul 2;10(8):1187-1192. doi: 10.1021/acsmedchemlett.9b00221. eCollection 2019 Aug 8.
The programmed cell death protein 1 (PD-1) signaling axis is among the most important therapeutic targets in modern oncology. Aurigene Discovery Technologies Ltd. (Aurigene) has patented a series of peptidomimetic small molecules derived from the PD-1 protein sequence for use in targeting the interaction between PD-1 and its ligand, PD-L1. We evaluated three of Aurigene's most potent compounds in SPR binding assays. Our results showed that these compounds-each of which is known to be potently effective in a splenocyte recovery assay-do not directly inhibit the PD-1/PD-L1 interaction nor do they appear to bind to either of the constituent proteins, indicating that another mechanism is at play. As a result of these studies and upon consideration of structural features within the PD-1/PD-L1 complex, we hypothesize that the Aurigene molecules may interact with a currently unknown protein capable of regulating the PD-1 axis.
程序性细胞死亡蛋白1（PD-1）信号轴是现代肿瘤学中最重要的治疗靶点之一。奥瑞金发现技术有限公司（Aurigene）已为一系列源自PD-1蛋白序列的拟肽小分子申请了专利，用于靶向PD-1与其配体PD-L1之间的相互作用。我们在表面等离子体共振（SPR）结合试验中评估了奥瑞金的三种最有效的化合物。我们的结果表明，这些化合物——每一种在脾细胞恢复试验中都已知具有强效作用——既不直接抑制PD-1/PD-L1相互作用，也似乎不与任何一种组成蛋白结合，这表明存在另一种作用机制。基于这些研究并考虑到PD-1/PD-L1复合物的结构特征，我们推测奥瑞金分子可能与一种目前未知的、能够调节PD-1轴的蛋白相互作用。
