通过在葡聚糖支架上显示多价小分子配体,实现溶酶体对细胞外蛋白质的转运和降解。

IF 5.5 2区 化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Biomacromolecules Pub Date : 2025-01-13 Epub Date: 2024-12-13 DOI:10.1021/acs.biomac.4c01603
Benoit Louage, Demi Defreyne, Heleen Lauwers, Jamie De Baere, Annemiek Uvyn, Haixia Peng, Yong Chen, Bruno G De Geest
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引用次数: 0

摘要

靶向蛋白降解(TPD)标志着药物开发从传统的抑制到完全去除病理蛋白的转变。传统的TPD技术针对细胞内目标蛋白(POIs)进行降解,但对细胞外细胞表面和可溶性蛋白(人类蛋白质组的重要组成部分)无效。最近的进展涉及在POI和细胞表面溶酶体运输受体之间形成三元复合物,将POI引导到溶酶体进行降解。我们报道了DEXtran转运嵌合体(DEXTRACs),该嵌合体包括模型POI和不依赖阳离子的甘露糖-6-磷酸受体(CI-M6PR)溶酶体转运受体的合成小分子配体的多个拷贝。这些配体沿着右旋糖酐骨架排列。我们证明了DEXTRACs利用多价性,其功效取决于葡聚糖链长度和配体密度,以形成高亲和力的三元配合物。我们的体外研究证实,DEXTRACs将目标POI运输到溶酶体并促进其降解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Lysosomal Trafficking and Degradation of Extracellular Proteins via Multivalent Small Molecule Ligand Display on Dextran Scaffolds.

Targeted protein degradation (TPD) marks a shift in drug development from conventional inhibition to the complete removal of pathological proteins. Traditional TPD technologies target intracellular proteins of interest (POIs) for degradation but are ineffective against extracellular cell surface and soluble proteins, a significant portion of the human proteome. Recent advances involve the formation of ternary complexes between a POI and a cell surface lysosomal trafficking receptor, directing POIs to lysosomes for degradation. We report on DEXtran TRAfficking Chimeras (DEXTRACs) comprising multiple copies of synthetic small molecule ligands for a model POI and the cation-independent mannose-6-phosphate receptor (CI-M6PR) lysosomal trafficking receptor. These ligands are arranged along the dextran backbones. We demonstrate that DEXTRACs leverage multivalency with their efficacy dependent on the dextran chain length and ligand density to form high-avidity ternary complexes. Our in vitro studies confirmed that DEXTRACs traffic the target POI to lysosomes and facilitate its degradation.

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来源期刊
Biomacromolecules
Biomacromolecules 化学-高分子科学
CiteScore
10.60
自引率
4.80%
发文量
417
审稿时长
1.6 months
期刊介绍: Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine. Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.
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