靶向蛋白降解技术及其在疾病治疗中的研究进展

Advances of targeted protein degradation technology and its applications in diseases therapy

摘要:

靶向蛋白降解 (Targeted protein degradation，TPD) 技术利用细胞内天然存在的两大蛋白降解系统：泛素化-蛋白酶体系统与溶酶体降解途径实现对疾病相关蛋白的特异、高效降解，从而达到疾病治疗的效果。相较于传统的小分子抑制剂，基于TPD技术的药物在靶点蛋白的选择上限制性更小，能够作用于“无成药性”的蛋白，从而拥有更为丰富的靶点库。与在基因、mRNA层面干扰蛋白表达的技术相比，TPD药物具有特异、快速以及不受蛋白翻译后修饰约束等特点。在过去的20年里，基于TPD技术的各类降解系统层出不穷，相关研究成果在近些年呈爆发式增长，更令人兴奋的是，2019年两种基于TPD技术的治疗性药物进入临床阶段并初步显示出良好的治疗效果。虽然TPD技术的发展处于起步阶段，目前仍存在诸多缺陷，但凭借其独有的优势，在不久的将来，该技术必将成为药物研发的主要手段之一，同时，也将给学术界和产业界带来前所未有的机遇。本综述详细介绍了基于TPD技术的不同降解系统的研究现状，阐述了各系统在疾病治疗中的应用，系统地总结了各自的优势和不足，以期为TPD技术在科学研究和药物研发中的进一步应用提供理论指导。

关键词:泛素化-蛋白酶体系统，蛋白降解靶向嵌合体，溶酶体降解途径，疾病治疗

Abstract:

Targeted protein degradation (TPD) technology facilitates specific and efficient degradation of disease-related proteins through hijacking the two major protein degradation systems in mammalian cells: ubiquitin-proteasome system and lysosome pathway. Compared with traditional small molecule-inhibitors, TPD-based drugs exhibit the characteristics of a broader target spectrum. Compared with techniques interfere with protein expression on the gene and mRNA level, TPD-based drugs are target-specific, efficaciously rapid, and not constrained by post-translational modification of proteins. In the past 20 years, various TPD-based technologies have been developed. Most excitingly, two TPD-based therapeutic drugs have been approved by FDA for phase Ⅰ clinical trials in 2019. Despite of the early stage characteristics and various obstructions of the TPD technology, it could serve as a powerful tool for the development of novel drugs. This review summarizes the advances of different degradation systems based on TPD technologies and their applications in disease therapy. Moreover, the advantages and challenges of various technologies were discussed systematically, with the aim to provide theoretical guidance for further application of TPD technologies in scientific research and drug development.

Key words:ubiquitin-proteasome system, proteolysis targeting chimeras (PROTAC), lysosomal degradation pathway, disease therapy