Bispecific Aptamer Induced Artificial Protein-Pairing: A Strategy for Selective Inhibition of Receptor Function
Bispecific Aptamer Induced Artificial Protein-Pairing: A Strategy for Selective Inhibition of Receptor Function
复制标题
双特异性适体诱导的人工蛋白质配对：选择性抑制受体功能的策略
DOI：
10.1021/jacs.9b05123
复制
发表时间：
2019
影响因子：
15
通讯作者：
Yang Huanghao
中科院分区：
文献类型：
--
作者：
Wang Liping;Liang Hong;Sun Jin;Liu Yichang;Li Jinyu;Li Jingying;Li Juan;Yang Huanghao
细胞表面受体在调节细胞内信号转导中发挥着关键作用，使其成为重要的药物靶点。然而，开发选择性且有效的调节受体功能的策略仍然具有挑战性。在此，我们开发了一种称为双特异性适体诱导的人工蛋白质配对的策略，以选择性调节受体功能。在该策略中，双特异性适体探针充当分子介体，与靶受体蛋白和配对蛋白结合，从而使两种蛋白在活细胞膜上紧密接近。重要的是，配对蛋白不仅可以作为增强细胞选择性的癌症生物标志物，还可以作为阻断助剂，通过强空间位阻效应抑制靶受体功能。与单适体介导的调节相比，所提出的双特异性适体探针在受体功能和下游信号通路的选择性和有效调节方面提供了实质性改进。这项工作提供了一种通用的方法来设计可以调节受体功能的分子介质，从而为开发新型治疗药物提供了新途径。
Cell surface receptors play a critical role in modulating intracellular signal transduction, making them important drug targets. However, it remains challenging to develop a selective and efficient strategy for regulating receptor function. Herein, we develop a strategy, called bispecific aptamer induced artificial protein-pairing, to selectively regulate receptor function. In this strategy, bispecific aptamer probes act as molecular mediators to bind to both a target receptor protein and a paired protein, which brings the two proteins into close proximity on the living cell membrane. Importantly, the paired proteins work not only as a cancer biomarker for enhancing cell selectivity but also as a blocking assistant to inhibit target receptor function via strong steric hindrance effect. Compared with single-aptamer-mediated regulation, the proposed bispecific aptamer probes afford substantial improvement in selective and efficient regulation of receptor function and downstream signaling pathways. This work offers a versatile methodology to design molecular mediators that can modulate receptor function, thereby providing a new way for developing novel therapeutic drugs.