中国科学院深圳先进技术研究院耿晋团队报道了溶酶体靶向嵌合体促进Glut1促进靶向蛋白降解。相关研究成果于2024年6月20日发表在《美国化学会杂志》。

靶向蛋白质降解技术在生物医学中具有巨大潜力，特别是在治疗肿瘤和其他蛋白质相关疾病方面。利用分子胶和PROTAC技术对细胞内蛋白质降解的研究处于领先地位，而通过溶酶体途径降解膜蛋白和细胞外蛋白质的研究仍处于临床前阶段。有用靶标的缺乏极大地限制了技术进步，因此有必要探索新的、潜在有效的靶向溶酶体降解方法。

该文中，研究人员使用葡萄糖转运蛋白Glut1作为一种创新的溶酶体靶向受体，并设计了Glut1促进溶酶体降解（GFLD）策略。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抗体-糖低聚物缀合物作为溶酶体靶向蛋白降解分子，用于治疗PD-L1高表达的三阴性癌症。葡萄糖转运蛋白Glut1作为溶酶体靶向受体，可能在未来表现出更广泛的药物开发潜力。

附：英文原文

Title: Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation

Author: Jinyan Luo, Quan Gao, Kui Tan, Shiling Zhang, Weiwei Shi, Lei Luo, Zhiying Li, Ghada E. Khedr, Jie Chen, Youwei Xu, Ming Luo, Qi Xing, Jin Geng

Issue&Volume: June 20, 2024

Abstract: 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.

DOI: 10.1021/jacs.4c02463

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c02463