Hu Kuan, Xie Lin, Hanyu Masayuki, Zhang Yiding, Li Lingyun, Ma Xiaohui, Nagatsu Kotaro, Suzuki Hisashi, Wang Weizhi, Zhang Ming-Rong
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology Chiba, 263-8555 Japan
School of Chemistry and Chemical Engineering, Beijing Institute of Technology Beijing 100081 P. R. China
RSC Chem Biol. 2020 Aug 27;1(4):214-224. doi: 10.1039/d0cb00070a. eCollection 2020 Oct 1.
Interface peptides that mediate protein-protein interactions (PPI) are a class of important lead compounds for designing PPI inhibitors. However, their potential as precursors for radiotracers has never been exploited. Here we report that the interface peptides from programmed death-ligand 1 (PD-L1) can be used in positron emission tomography (PET) imaging of programmed cell death 1 (PD-1) with high accuracy and sensitivity. Moreover, the performance differentiation between murine PD-L1 derived interface peptide (mPep-1) and human PD-L1 derived interface peptide (hPep-1) as PET tracers for PD-1 unveiled an unprecedented role of a non-critical residue in target binding, highlighting the significance of PET imaging as a companion diagnostic in drug development. Collectively, this study not only provided a first-of-its-kind peptide-based PET tracer for PD-1 but also conveyed a unique paradigm for developing imaging agents for highly challenging protein targets, which could be used to identify other protein biomarkers involved in the PPI networks.
介导蛋白质-蛋白质相互作用（PPI）的界面肽是设计PPI抑制剂的一类重要先导化合物。然而，它们作为放射性示踪剂前体的潜力从未被开发利用过。在此我们报告，来自程序性死亡配体1（PD-L1）的界面肽可用于程序性细胞死亡1（PD-1）的正电子发射断层扫描（PET）成像，具有高准确性和高灵敏度。此外，作为PD-1的PET示踪剂，源自小鼠PD-L1的界面肽（mPep-1）和源自人类PD-L1的界面肽（hPep-1）之间的性能差异揭示了一个非关键残基在靶点结合中的前所未有的作用，突出了PET成像作为药物开发中伴随诊断的重要性。总的来说，这项研究不仅为PD-1提供了首个基于肽的PET示踪剂，还为开发针对极具挑战性的蛋白质靶点的成像剂传达了一种独特的范例，可用于识别参与PPI网络的其他蛋白质生物标志物。
