湖南大学谭蔚泓小组取得一项突破。他们研制了用于膜蛋白降解的整合素促进的双特异性适配体嵌合体。2024年9月3日，国际知名学术期刊《美国化学会杂志》发表了这一成果。

溶酶体靶向嵌合体(LYTACs)的出现，代表了一种基于溶酶体途径的膜蛋白降解策略，在疾病干预和治疗中引起了广泛的关注。然而，共用的溶酶体靶向受体(LTRs)在不同细胞系中的表达水平不同，这限制了LYTAC的广泛应用。

为了克服这一困难，课题组人员报道了整合素α3β1 (ITGA3B1)促进的，双特异性适体嵌合体(ITGBACs)作为膜蛋白降解的平台的发展。ITGBACs由两个适体组成，一个靶向ITGA3B1，另一个与膜相关蛋白(POI)结合，有效地将POI转运到溶酶体中进行降解。

他们的研究结果表明，ITGBACs有效地消除病理膜蛋白，如CD71和PTK7，诱导显著的细胞周期阻滞和凋亡，并显著抑制肿瘤模型中的肿瘤生长。因此，这项工作提供了一个新的和通用的膜蛋白降解平台，提供了一个有希望的基于肿瘤特异性的LTR的靶向治疗的平台。

附：英文原文

Title: Development of Integrin-Facilitated Bispecific Aptamer Chimeras for Membrane Protein Degradation

Author: Weidi Sun, Hui Zhang, Wanlin Xie, Lele Ma, Yang Dang, Yuan Liu, Ling Li, Fengli Qu, Weihong Tan

Issue&Volume: September 3, 2024

Abstract: 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.

DOI: 10.1021/jacs.4c04794

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c04794