湖南大学刘艳岚团队开发了用于广谱衰老治疗的溶酶体代谢靶向分子前药对细胞衰老的空间限制干预方法。相关研究成果于2022年1月17日发表在国际顶尖学术期刊《德国应用化学》。

衰老细胞（SnCs）的特异性干预正在成为对抗衰老和年龄相关疾病的有力手段。标准化方法通常是针对SnC相关的信号通路设计的，然而SnCs中的信号通路是动态变化的，并且具有高度异质性，显著限制了其有效性。

该文中，研究人员提出了一种针对溶酶体功能障碍的特制分子前药，这是几乎所有类型的SnsC都具有的独特特征。前体药物包括三个模块，所有模块均以SnCs中改变的溶酶体程序为目标，即：一个针对升高溶酶体含量的识别单元，一个可被激活溶酶体酶切割的连接体，以及一个针对增加的溶酶体膜敏感性的溶酶体致敏剂。该空间受限的设计能够杀死广谱SnCs，比非SnCs具有更高的特异性。除了在体内的益处外，该工作还提供了一种方法，可显著扩大衰老治疗在各种疾病中的适用性。

附：英文原文

Title: Spatially Confined Intervention of Cellular Senescence by a Lysosomal Metabolism Targeting Molecular Prodrug for Broad-Spectrum Senotherapy

Author: Yanlan Liu, Yinghao Xia, Jili Li, Linlin Wang, Xiyuan Luo, Yuqi Xie

Issue&Volume: 2022-01-17

Abstract: Specific intervention of senescent cells (SnCs) is emerging as a powerful means to counteract aging and age-related diseases. Canonical methods are generally designed to target SnC-associated signaling pathways, which are however dynamically changing and highly heterogeneous in SnCs, significantly limiting the effectiveness. Here, we present a tailor-made molecular prodrug targeting lysosome dysfunction, a unique feature shared by virtually all types of SnCs.The prodrug comprises three modules all targeting the altered lysosomal programs in SnCs, namely, a recognizing unit towards the elevated lysosome content, a linker cleavable by the activated lysosomal enzyme, and a lysosomotropic agent targeting the increased lysosomal membrane sensitivity. This spatially confined design enables killing broad-spectrum SnCs, with high specificity over non-SnCs. Along with in vivo benefits, this work offers a way to significantly expand the applicability of senotherapy in a wide range of diseases.

DOI: 10.1002/anie.202115764

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202115764