自噬
溶酶体
蛋白酶体
蛋白质降解
蛋白质水解
泛素
计算生物学
细胞生物学
范围(计算机科学)
降级(电信)
化学
生物
生物化学
计算机科学
酶
电信
基因
细胞凋亡
程序设计语言
作者
Katelyn Cassidy,Heng Zhao
出处
期刊:Biochemistry
[American Chemical Society]
日期:2021-09-27
卷期号:62 (3): 580-587
被引量:7
标识
DOI:10.1021/acs.biochem.1c00330
摘要
The advent of multi-specific targeted protein degradation (TPD) therapies has made it possible to drug targets that have long been considered to be inaccessible. For this reason, the foremost TPD modalities - molecular glues and proteolysis targeting chimeras (PROTACs) -have been widely adopted and developed in therapeutic programs across the pharmaceutical and biotechnology industries. While there are many clear advantages to these two approaches, there are also blind spots. Specifically, PROTACs and molecular glues are inherently mechanistically analogous in that targets of both are degraded via the 26s proteasome; however, not all disease-relevant targets are suitable for ubiquitin proteasome system (UPS)-mediated degradation. The alternative mammalian protein degradation pathway, the autophagy-lysosome system (or ALS), is capable of degrading targets that elude the UPS such as long-lived proteins, insoluble protein aggregates, and even abnormal organelles. Emerging TPD strategies- such as ATTEC, AUTAC, and LYTAC- take advantage of the substrate diversity of the ALS to greatly expand the clinical utility of TPD. In this Perspective, we will discuss the array of current TPD modalities, with a focus on critical evaluation of these novel ALS-mediated degradation techniques.
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