基于生物的降解剂 - 靶向蛋白降解的不断扩展的工具包。
Biologics-based degraders - an expanding toolkit for targeted-protein degradation.
机构信息
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Biologics Engineering, R&D, AstraZeneca, Gaithersburg, MD, USA.
Biologics Engineering, R&D, AstraZeneca, Cambridge, UK.
出版信息
Curr Opin Biotechnol. 2022 Dec;78:102807. doi: 10.1016/j.copbio.2022.102807. Epub 2022 Sep 27.
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.
靶向蛋白降解（TPD）是一种广泛应用于生物研究和治疗开发的蛋白质组编辑工具。与单独的功能抑制相比，TPD 具有几个优势，包括能够靶向以前无法治疗的蛋白质，以及对蛋白质活性进行实质性和持续的敲除。各种小分子方法利用内源性蛋白质降解机制，但仅限于具有细胞质结构域和合适结合口袋的蛋白质。最近，基于生物制剂的方法通过允许访问细胞外和表面暴露的蛋白质并提高靶标特异性，扩展了 TPD 工具包。在这里，我们总结了最近利用生物制剂通过泛素-蛋白酶体系统或溶酶体降解途径来消耗蛋白质的进展，并讨论了它们作为潜在治疗干预措施的有效递送途径。
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