Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
J Am Chem Soc. 2024 Jul 3;146(26):17728-17737. doi: 10.1021/jacs.4c02463. Epub 2024 Jun 20.
Targeted protein degradation technology holds great potential in biomedicine, particularly in treating tumors and other protein-related diseases. Research on intracellular protein degradation using molecular glues and PROTAC technology is leading, while research on the degradation of membrane proteins and extracellular proteins through the lysosomal pathway is still in the preclinical stage. The scarcity of useful targets is an immense limitation to technological advancement, making it essential to explore novel, potentially effective approaches for targeted lysosomal degradation. Here, we employed the glucose transporter Glut1 as an innovative lysosome-targeting receptor and devised the Glut1-Facilitated Lysosomal Degradation (GFLD) strategy. We synthesized potential Glut1 ligands via reversible addition-fragmentation chain transfer (RAFT) polymerization and acquired antibody-glycooligomer conjugates through bioorthogonal reactions as lysosome-targeting protein degradation molecules, utilized in the management of PD-L1 high-expressing triple-negative breast cancer. The glucose transporter Glut1 as a lysosome-targeting receptor exhibits potential for the advancement of a broader array of medications in the future.
靶向蛋白降解技术在生物医药领域具有巨大的潜力，特别是在治疗肿瘤和其他与蛋白质相关的疾病方面。使用分子胶和 PROTAC 技术研究细胞内蛋白质降解的研究处于领先地位，而通过溶酶体途径研究膜蛋白和细胞外蛋白质的降解仍处于临床前阶段。有用靶点的稀缺性是技术进步的巨大限制，因此有必要探索新的、潜在有效的靶向溶酶体降解方法。在这里，我们将葡萄糖转运蛋白 Glut1 用作创新的溶酶体靶向受体，并设计了 Glut1 促进的溶酶体降解（GFLD）策略。我们通过可逆加成-断裂链转移（RAFT）聚合合成了潜在的 Glut1 配体，并通过生物正交反应获得了抗体糖缀合物作为溶酶体靶向蛋白降解分子，用于管理 PD-L1 高表达的三阴性乳腺癌。葡萄糖转运蛋白 Glut1 作为溶酶体靶向受体，未来可能会有更广泛的药物得到发展。
