Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China.
Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
Bioorg Chem. 2023 Dec;141:106908. doi: 10.1016/j.bioorg.2023.106908. Epub 2023 Oct 7.
Lysosome-targeting chimeras (LYTACs) have emerged as a promising technique to extend the scope of targeted protein degradation to extracellular proteins, e.g., secreted proteins and membrane-anchored proteins. However, up to now, only a small number of lysosomal targeting receptors (LTRs), such as cation-independent mannose 6-phosphate receptor (CI-M6PR) and asialoglycoprotein receptor (ASGPR), were reported to build LYTACs for degradation of extracellular proteins. Therefore, it is important to explore more functionalized ligands for the relevant LTRs to expand the LYTAC framework. Herein, we demonstrate a new LTR ligand-glucagon like peptide 1 (GLP-1) based targeted degradation platform, termed GLP-1 receptor-targeting chimeras (GLP-1-LYTAC). GLP-1-LYTACs are formed by conjugating GLP-1 with targeted binder (such as antibody) through Click Chemistry, showing efficiently lysosomal degradation of both extracellular proteins (GFP and Neutravidin) as well as cell membrane proteins (EGFR and PD-L1). We believe that this novel GLP-1-LYTAC will open up a new dimension for targeted protein breakdown.
溶酶体靶向嵌合体 (LYTAC) 已成为一种有前途的技术，可以将靶向蛋白降解的范围扩展到细胞外蛋白，例如分泌蛋白和膜锚定蛋白。然而，到目前为止，只有少数溶酶体靶向受体 (LTR)，如阳离子非依赖性甘露糖 6-磷酸受体 (CI-M6PR) 和去唾液酸糖蛋白受体 (ASGPR)，被报道用于构建用于降解细胞外蛋白的 LYTAC。因此，探索更多功能化的配体对于相关 LTR 以扩展 LYTAC 框架非常重要。在此，我们展示了一种新的 LTR 配体-胰高血糖素样肽 1 (GLP-1) 基于靶向降解的平台，称为 GLP-1 受体靶向嵌合体 (GLP-1-LYTAC)。GLP-1-LYTAC 通过点击化学将 GLP-1 与靶向结合物（如抗体）连接形成，能够有效降解细胞外蛋白（GFP 和 Neutravidin）和细胞膜蛋白（EGFR 和 PD-L1）的溶酶体降解。我们相信这种新型 GLP-1-LYTAC 将为靶向蛋白降解开辟新的维度。
