开发整合素促进的双特异性适体嵌合体用于膜蛋白降解。
Development of Integrin-Facilitated Bispecific Aptamer Chimeras for Membrane Protein Degradation.
发表日期：2024 Sep 03
作者：
Weidi Sun, Hui Zhang, Wanlin Xie, Lele Ma, Yang Dang, Yuan Liu, Ling Li, Fengli Qu, Weihong Tan
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
溶酶体靶向嵌合体（LYTAC）的出现代表了一种基于溶酶体途径的膜蛋白降解的有前景的策略，在疾病干预和治疗中引起了广泛关注。然而，常用的溶酶体靶向受体（LTR）在不同细胞系中的表达水平有所不同，从而限制了LYTAC的广泛应用。为了克服这一困难，我们在此报告了整合素α3β1（ITGA3B1）促进的双特异性适体嵌合体（ITGBAC）的开发，作为膜蛋白降解的平台。 ITGBAC 由两个适体组成，一个针对 ITGA3B1，另一个与感兴趣的膜相关蛋白 (POI) 结合，有效地将 POI 转运到溶酶体中进行降解。我们的研究结果表明，ITGBAC 能有效消除病理性膜蛋白，如 CD71 和 PTK7，诱导显着的细胞周期停滞和细胞凋亡，并显着抑制荷瘤小鼠模型中的肿瘤生长。因此，这项工作提供了一种新颖且多功能的膜蛋白降解平台，提供了一种基于肿瘤特异性LTR的有前景的靶向治疗。
The emergence of lysosome-targeting chimeras (LYTACs), which represents a promising strategy for membrane protein degradation based on lysosomal pathways, has attracted much attention in disease intervention and treatment. However, the expression level of commonly used lysosome-targeting receptors (LTRs) varies in different cell lines, thus limiting the broad applications of LYTACs. To overcome this difficulty, we herein report the development of integrin α3β1 (ITGA3B1)-facilitated bispecific aptamer chimeras (ITGBACs) as a platform for the degradation of membrane proteins. ITGBACs consist of two aptamers, one targeting ITGA3B1 and another binding to the membrane-associated protein of interest (POI), effectively transporting the POI into lysosomes for degradation. Our findings demonstrate that ITGBACs effectively eliminate pathological membrane proteins, such as CD71 and PTK7, inducing significant cell-cycle arrest and apoptosis and markedly inhibiting tumor growth in tumor-bearing mice models. Therefore, this work provides a novel and versatile membrane protein degradation platform, offering a promising targeted therapy based on tumor-specific LTRs.