PROTAC药物研究及其应用

Yixin Xu
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引用次数: 0

摘要

目前,可以作为药物使用的蛋白质靶点非常少,大约15%的蛋白质受到小分子和生物大分子的调控,而85%的蛋白质目前没有药物靶点,无法受到小分子和生物大分子的调控。蛋白水解靶向嵌合体(Proteolytic targeting chimeras, protacs)可以通过蛋白酶体降解许多非药物靶蛋白,从而调节其调控作用。靶向嵌合体的蛋白质降解是药物研究和开发的一个新兴方向。传统抑制剂具有阻断作用,导致耐药和脱靶现象。然而,该技术通过26S蛋白酶系统降解目标蛋白。在结构上,PROTAC由三部分组成:左端是与靶蛋白结合的配体,右端是与泛素连接酶连接的配体,中间通过“Linker”连接。在患者体内,PROTAC一端连接E3泛素连接酶,另一端连接待降解的靶蛋白。通过多轮泛素化,形成泛素链,实现UPS系统降解靶蛋白。PROTAC小分子在疾病治疗中具有广阔的应用前景。与传统的小分子药物不同,它们不会破坏蛋白质的功能,而是完全降解蛋白质。PROTAC可以被循环利用,我们感兴趣的蛋白质通过蛋白酶体被多泛素化和降解。解离的PROTAC还可以启动新的降解,这是对抗癌细胞的重要突破。例如,我们可以设计一种PROTAC来劫持癌细胞无限增殖所需的蛋白质,使其降解并抑制癌细胞的生长。PROTAC药物的开发和临床应用有待进一步探索。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PROTAC Pharmaceutical Research and its Applications
At present, there are very few protein targets that can be used as drugs, with approximately 15% of proteins being regulated by small molecules and biomacromolecules, while 85% of proteins currently do not have drug targets and cannot be regulated by small molecules and biomacromolecules. Proteolytic targeting chimeras (protacs) can degrade many non-pharmacological target proteins through proteasomes, thereby regulating their regulatory effects. Protein degradation targeting chimeras is an emerging direction in drug research and development. Traditional inhibitors have a blocking effect, leading to drug resistance and off target phenomena. However, this technology degrades the target protein through a 26S protease system. Structurally, PROTAC consists of three parts: the left end is a ligand that binds to the target protein, the right end is a ligand that connects to ubiquitin ligase, and the middle is connected through a "Linker". In the patient's body, one end of PROTAC is connected to E3 ubiquitin ligase, and the other end is connected to the target protein to be degraded. Through multiple rounds of ubiquitination, a ubiquitin chain is formed, achieving the UPS system to degrade the target protein. PROTAC small molecules have great prospects in the treatment of diseases. Unlike traditional small molecule drugs, they do not destroy the function of proteins, but completely degrade them. And PROTAC can be recycled, and the proteins of interest are polyubiquitinated and degraded through proteasomes. The dissociated PROTAC can also initiate new degradation, which is an important breakthrough in the fight against cancer cells. For example, we can design a PROTAC to hijack the protein required for unlimited proliferation of cancer cells, so that it can be degraded and inhibit the growth of cancer cells. Further exploration is needed for the development and clinical application of PROTAC drugs.
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