Yujun Ning, Bin Li, Weishuai Chen, Langxia Feng, Xuedong Huang and Baohong Liu*,
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引用次数: 0
Abstract
Targeted protein degradation (TPD) offered a riveting therapeutic paradigm to eradicate pathogenesis-relevant proteins, especially those belonging to the once-considered undruggable proteome. Considering that adenosine triphosphate (ATP) is the primary energy source for cell activities and lysosomes are important ATP storage sites, herein, the first example of dual-function tetrahedral DNA framework-based lysosome-targeting chimeras (TDF-LYTACs) is proposed for elucidating the correlation between extracellular protein degradation via the lysosome pathway and the fluctuations in intracellular ATP levels. In our study, platelet-derived growth factor (PDGF), a driver of cancer invasion and metastasis, was chosen as the protein of interest. To achieve multifunctionality, we employed a tetrahedral DNA framework formed by an aptamer of PDGF, human apurinic/apyrimidinic endonuclease 1 (APE1)-triggered ATP probes, and a ligand of the cell-surface lysosome-shuttling receptor (IGFIIR). TDF-LYTACs efficiently and quickly shuttled PDGF proteins to lysosomes, degraded them through the lysosomal pathway, and further visualized the intracellular ATP level synchronously. Furthermore, we found a significant correlation between the degradation efficiency of PDGF and intracellular ATP levels over time; that is, a higher ATP level corresponded to higher degradation efficiency and vice versa. We anticipate that our versatile TDF-LYTACs will offer a perspective for degrading multifunctional extracellular proteins.
靶向蛋白降解(Targeted protein degradation, TPD)为根除与发病相关的蛋白,特别是那些曾经被认为是不可药物的蛋白质组提供了一种极具吸引力的治疗范式。考虑到三磷酸腺苷(ATP)是细胞活动的主要能量来源,而溶酶体是重要的ATP储存位点,本文提出了基于双功能四面体DNA框架的溶酶体靶向嵌合体(TDF-LYTACs)的第一个例子,以阐明通过溶酶体途径的细胞外蛋白质降解与细胞内ATP水平波动之间的相关性。在我们的研究中,血小板衍生生长因子(PDGF)是一种癌症侵袭和转移的驱动因子,被选为感兴趣的蛋白质。为了实现多功能性,我们采用了由PDGF适配体、人类无嘌呤/无嘧啶核酸内切酶1 (APE1)触发的ATP探针和细胞表面溶酶体穿梭受体(IGFIIR)配体组成的四面体DNA框架。TDF-LYTACs高效、快速地将PDGF蛋白运送到溶酶体,通过溶酶体途径降解PDGF蛋白,并进一步同步可视化细胞内ATP水平。此外,我们发现PDGF的降解效率与细胞内ATP水平之间随时间的显著相关性;即ATP水平越高,降解效率越高,反之亦然。我们期望我们的多功能TDF-LYTACs将为降解多功能细胞外蛋白提供一个前景。
期刊介绍:
ACS Nano, published monthly, serves as an international forum for comprehensive articles on nanoscience and nanotechnology research at the intersections of chemistry, biology, materials science, physics, and engineering. The journal fosters communication among scientists in these communities, facilitating collaboration, new research opportunities, and advancements through discoveries. ACS Nano covers synthesis, assembly, characterization, theory, and simulation of nanostructures, nanobiotechnology, nanofabrication, methods and tools for nanoscience and nanotechnology, and self- and directed-assembly. Alongside original research articles, it offers thorough reviews, perspectives on cutting-edge research, and discussions envisioning the future of nanoscience and nanotechnology.