Bispecific Aptamer Induced Artificial Protein-Pairing: A Strategy for Selective Inhibition of Receptor Function

• Published in: Journal of the American Chemical Society Vol. 141; no. 32; pp. 12673 - 12681
• Main Authors: Wang, Liping, Liang, Hong, Sun, Jin, Liu, Yichang, Li, Jinyu, Li, Jingying, Li, Juan, Yang, Huanghao
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.08.2019
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.9b05123

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.