Biologics-based degraders - an expanding toolkit for targeted-protein degradation.
Biologics-based degraders - an expanding toolkit for targeted-protein degradation.
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DOI：
10.1016/j.copbio.2022.102807
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发表时间：
2022-09
影响因子：
7.7
通讯作者：
D. VanDyke;Jonathan D. Taylor;Kyle J Kaeo;J. Hunt;Jamie B. Spangler
中科院分区：
文献类型：
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作者：
D. VanDyke;Jonathan D. Taylor;Kyle J Kaeo;J. Hunt;Jamie B. Spangler
聚焦靶向蛋白质降解支持基础发现和药物开发。基于生物的降解剂靶向细胞内，细胞外，生物方法促进组织靶向和异构体特异性降解。基于生物的降解剂利用蛋白酶体和溶酶体降解。正在开发新的策略以在体内递送基于生物的降解剂。靶向蛋白降解（TPD）是生物学研究和治疗开发的广泛有用的蛋白质组编辑工具。TPD提供了几个优于单独功能抑制的优点，包括靶向先前不可用药的蛋白质的能力和蛋白质活性的实质性和持续敲除。各种小分子方法劫持内源性蛋白质降解机制，但限于具有胞质结构域和合适的结合口袋的蛋白质。最近，基于生物学的方法通过允许获得细胞外和表面暴露的蛋白质并增加靶特异性来扩展TPD工具箱。在这里，我们总结了最近的进展，在使用生物制剂消耗蛋白质通过泛素-蛋白酶体系统或溶酶体降解途径，并讨论其有效的交付作为潜在的治疗干预措施的途径。
HighlightsTargeted-protein degradation supports fundamental discovery and drug development.Biologics-based degraders target intracellular, extracellular, and membrane proteins.Biologic approaches facilitate tissue-targeting and isoform-specific degradation.Biologics-based degraders utilize both proteasomal and lysosomal degradation.New strategies are being developed to deliver biologics-based degraders in vivo.Targeted protein degradation (TPD) is a broadly useful proteome editing tool for biological research and therapeutic development. TPD offers several advantages over functional inhibition alone, including the ability to target previously undruggable proteins and the substantial and sustained knockout of protein activity. A variety of small molecule approaches hijack endogenous protein degradation machinery, but are limited to proteins with a cytosolic domain and suitable binding pocket. Recently, biologics-based methods have expanded the TPD toolbox by allowing access to extracellular and surface-exposed proteins and increasing target specificity. Here, we summarize recent advances in the use of biologics to deplete proteins through either the ubiquitin–proteasome system or the lysosomal degradation pathway, and discuss routes to their effective delivery as potential therapeutic interventions.