Liu Xingui, Ciulli Alessio
Centre for Targeted Protein Degradation, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, 1 James Lindsay Place, Dundee DD1 5JJ, United Kingdom.
ACS Cent Sci. 2023 Jul 14;9(7):1269-1284. doi: 10.1021/acscentsci.3c00395. eCollection 2023 Jul 26.
Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of biological processes with high selectivity and has the potential to substantially expand the target space. A plethora of proximity-based modalities to target proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines the diverse mechanisms and molecules based on induced proximity, including protein degraders, blockers, and stabilizers, inducers of protein post-translational modifications, and agents for cell therapy, and discusses opportunities and challenges that the field must address to mature and unlock translation in biology and medicine.
分子 proximity 协调生物功能，而阻断现有的 proximity 是一种既定的治疗策略。相比之下，通过化学方法增强或创造新的 proximity 能够以高选择性调节生物过程，并有可能大幅扩大靶点范围。最近出现了大量通过多种方法靶向蛋白质的基于 proximity 的模式，为生物制药创新带来了机遇。本展望概述了基于诱导 proximity 的多种机制和分子，包括蛋白质降解剂、阻断剂和稳定剂、蛋白质翻译后修饰诱导剂以及细胞治疗药物，并讨论了该领域为实现成熟以及开启生物学和医学转化而必须应对的机遇和挑战。
