Dear Editor,

Targeted protein degradation (TPD) has emerged as a breakthrough strategy in revolutionizing drug discovery for the currently undruggable targets. However, E3 ligase-based targeted degradation chimeras, such as proteolysis-targeting chimeras (PROTACs), are limited by the specificity of E3 ligases and the requirement for ubiquitination.¹ Some innovative TPD strategies like LYTAC, AUTAC, ATTEC, AUTOTAC often rely predominantly on single degradation pathways, which restricts their versatility in degrading proteins across various cellular compartments.^2,3,4,5 In this context, it is imperative to establish a universal TPD platform that can harness degradation-related liquid–liquid phase-separated droplets, which are defined as degradation condensates, to effectively target a multitude of proteins of interest (POIs). Sequestosome 1 (p62 or SQSTM1) bodies are notable representatives of such degradation condensates, which bridge the gap between the ubiquitin–proteasome system (UPS) and the autophagy-lysosome pathway (ALP) by initiating liquid–liquid phase separation (LLPS) to integrate degradation-related components.^6,7 In this study, we developed a highly modular and precise platform termed the P62 Degradation Factory based on a BI-specific Nanobody (PDF-Bin), in which an engineered nanobody bridges POIs to p62 bodies for subsequent breakdown.

亲爱的编辑，

靶向蛋白质降解（TPD）已成为彻底改变当前不可成药靶点的药物发现的突破性策略。然而，基于E3连接酶的靶向降解嵌合体，例如蛋白水解靶向嵌合体（PROTAC），受到E3连接酶的特异性和泛素化要求的限制。¹一些创新的 TPD 策略（例如 LYTAC、AUTAC、ATTEC、AUTOTAC）通常主要依赖于单一降解途径，这限制了它们在跨不同细胞区室降解蛋白质方面的多功能性。^2,3,4,5在这种背景下，建立一个通用的 TPD 平台势在必行，该平台可以利用与降解相关的液-液相分离液滴（定义为降解冷凝物）来有效地靶向多种感兴趣的蛋白质（兴趣点）。Sequestosome 1 (p62 或 SQSTM1) 体是此类降解凝聚物的著名代表，它通过启动液-液相分离 (LLPS) 来整合泛素-蛋白酶体系统 (UPS) 和自噬-溶酶体途径 (ALP) 之间的差距。与降解相关的成分。^6,7在这项研究中，我们开发了一个高度模块化和精确的平台，称为P 62 降解工厂，基于 BI 特异性 N抗体( PDF - Bin ) ，其中工程化纳米抗体将 POI 桥接到 p62 体以进行后续分解。