Recently, the team of Zhengyu Jiang/Xiaoke Guo/Qidong You from the School of Pharmacy of the University of China published a research paper titled Supramolecular Host-Guest Assemblies for Tunable and Modular Lysosome-Targeting Protein Degradation in the prestigious journal Angewandte Chemie International Edition online. Xuetao Chen, a postdoctoral fellow at the School of Pharmacy, and Tingting Wu and Yali Chen, master's students of the class of 2022, were the co-first authors of the paper, while Prof. Zhengyu Jiang, Xiaoke Guo and Qidong You were the co-corresponding authors, and China Pharmaceutical University (CPU) was the sole completion unit of the paper.
Targeted protein degradation technology has become an important frontier in small molecule drug development, especially the heterologous bifunctional molecule strategy represented by PROTACs and LYTACs, which provides a new pathway for the intervention of traditional “non-druggable” targets. Among them, LYTACs recruit the lysosomal pathway to achieve the degradation of extracellular or membrane proteins, but they rely on the fixed covalent linkage model, which has significant limitations in structure optimization, target switching, and spatial-temporal regulation. To address these challenges, the team proposed and constructed a novel degradation system based on supramolecular host-guest interactions, Host-Guest Bridged Lysosome-Targeting Chimeras (HGTACs). The system utilizes the stable and reversible non-covalent recognition between β-cyclodextrin (β-CD) and adamantane (Ada), and for the first time realizes the dynamic assembly and decoupling of the targeting destination protein recognition module and the lysosome-directed module, which allows the degradants to be rapidly assembled, flexibly adjusted, and finely controlled in terms of degradation efficiency according to targeting needs.
This study proposes a modular, reversible and adjustable novel protein degradation strategy, which successfully breaks through the design bottleneck of the traditional LYTAC covalent linkage configuration and provides a new paradigm with more flexibility for the targeted degradation of extracellular and membrane proteins, which is of great significance for expanding the application of host-guest chemistry in drug discovery.
This work was supported by the National Natural Science Foundation of China, the Basic Research Program of Jiangsu Province, the Xingdao Scholar Program of China Pharmaceutical University, the Fundamental Research Operating Expenses of the Central Universities, and the China Postdoctoral Science Foundation, etc.; and by the Key Laboratory of Innovative Drug Design and Pharmacogenetic Optimization of Jiangsu Province, and the Platform of the National Key Laboratory of Multi-targeted Natural Drugs.
Original link: https://doi.org/10.1002/anie.202506618
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