Gao Yanan, Bai Qingjie, Ren Youxiao, Shao Xintian, Zhang Mengrui, Wu Luling, Lewis Simon E, James Tony D, Chen Xiaoyuan, Chen Qixin
State Key Laboratory of Advanced Drug Delivery and Release Systems, School of Pharmaceutical Sciences, Neck-Shoulder and Lumbocrural Pain Hospital, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, PR China.
Department of Chemistry, University of Bath, Bath, BA2 7AY, U.K.
Angew Chem Int Ed Engl. 2025 Mar 3;64(10):e202421269. doi: 10.1002/anie.202421269. Epub 2025 Jan 22.
Mitophagy, particularly in the context of drugs that disrupt mitochondrial membrane potential (MMP), represents a critical focus in pharmacology. However, the discovery and evaluation of MMP-disrupting drugs are often hampered using commercially available marker molecules that target similar or identical zones. These markers can significantly interfere with, obscure, or amplify the functional effects of MMP-targeting drugs, frequently leading to clinical failures. In response to this challenge, we propose a "one-two punch" drug design strategy that integrates both target-zone drug functionality and non-target zone biological reporting within a single small-molecule drug. We have developed a novel proof-of-concept mitophagy self-check drug (MitoSC) that exhibits dual-color and dual-localization properties. The functional component of this system is a variable MitoSC that disrupts mitochondrial membrane potential (MMP) homeostasis, thereby inducing mitophagy. Upon activation, this component transforms into a blue-fluorescent monomer (MitoSC-fun) specifically within the mitochondrial target zone. Concurrently, the biological reporting component is represented by a red-fluorescent monomer (MitoSC-rep) that localizes to lysosomes, the non-target zone. As mitophagy progresses, the fluorescent signals from MitoSC-rep (lysosomes) and MitoSC-fun (mitochondria) converge, enabling real-time monitoring of the mitophagic process. This strategy combines potent drug functionality with robust biological reporting, thereby minimizing interference and eliminating the complexities associated with external detection. Our findings underscore the potential of a single-molecule drug to exert target-zone specific actions while simultaneously providing non-target zone self-checking, offering a new perspective for drug design.
线粒体自噬，尤其是在涉及破坏线粒体膜电位（MMP）的药物的背景下，是药理学中的一个关键研究重点。然而，使用靶向相似或相同区域的市售标记分子来发现和评估破坏MMP的药物常常受到阻碍。这些标记物会显著干扰、掩盖或放大靶向MMP药物的功能效应，经常导致临床失败。针对这一挑战，我们提出了一种“双拳出击”的药物设计策略，该策略将靶区药物功能和非靶区生物报告整合在单个小分子药物中。我们开发了一种新型的概念验证性线粒体自噬自检药物（MitoSC），它具有双色和双定位特性。该系统的功能成分是可变的MitoSC，它会破坏线粒体膜电位（MMP）稳态，从而诱导线粒体自噬。激活后，该成分会在线粒体靶区内特异性地转化为蓝色荧光单体（MitoSC-fun）。同时，生物报告成分由定位到溶酶体（非靶区）的红色荧光单体（MitoSC-rep）代表。随着线粒体自噬的进行，来自MitoSC-rep（溶酶体）和MitoSC-fun（线粒体）的荧光信号会汇聚，从而能够实时监测线粒体自噬过程。这种策略将强大的药物功能与强大的生物报告相结合，从而最大限度地减少干扰并消除与外部检测相关的复杂性。我们的研究结果强调了单分子药物在发挥靶区特异性作用的同时提供非靶区自检的潜力，为药物设计提供了新的视角。
