Membrane protein degradation is a cutting-edge field in targeted protein degradation (TPD). Herein, we developed glypican-3 (GPC3)-mediated lysosome-targeting chimeras (GLTACs) as a novel strategy for the targeted degradation of tumor-specific membrane proteins. GLTACs utilize tumor-specific expression and endocytosis properties of GPC3 to degrade membrane proteins. By conjugating a GPC3-targeting peptide with the ligand of protein of interest (POI), GLTACs induce the formation of a ternary complex that is internalized into lysosomes, leading to the degradation of the POI. The effectiveness and specificity of GLTACs were validated by designing PD-L1, c-Met, and FGFR1 degraders. In particular, GLTAC WP0 potently degraded PD-L1 and induced T-cell-mediated tumor killing against HepG2 cells, highlighting the potential therapeutic applications. The development of GLTAC technology expands the scope of TPD strategies and opens new avenues for discovering novel therapeutic modalities against challenging protein targets.

中文翻译：

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GPC3 介导的溶酶体靶向嵌合体 （GLTAC） 用于膜蛋白的靶向降解


膜蛋白降解是靶向蛋白降解 （TPD） 的一个前沿领域。在此，我们开发了 glypican-3 （GPC3） 介导的溶酶体靶向嵌合体 （GLTACs） 作为靶向降解肿瘤特异性膜蛋白的新策略。GLTAC 利用 GPC3 的肿瘤特异性表达和内吞特性来降解膜蛋白。通过将 GPC3 靶向肽与目标蛋白配体 （POI） 偶联，GLTAC 诱导形成内化到溶酶体中的三元复合物，从而导致 POI 降解。通过设计 PD-L1 、 c-Met 和 FGFR1 降解剂来验证 GLTACs 的有效性和特异性。特别是，GLTAC WP0 有效降解 PD-L1 并诱导 T 细胞介导的针对 HepG2 细胞的肿瘤杀伤，突出了潜在的治疗应用。GLTAC 技术的发展扩大了 TPD 策略的范围，并为发现针对具有挑战性的蛋白质靶标的新型治疗方式开辟了新的途径。