School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
College of Chemistry and Materials Science, Northwest University, Xi'an 710127, China.
Anal Chem. 2022 May 17;94(19):7092-7099. doi: 10.1021/acs.analchem.2c00859. Epub 2022 May 3.
Autophagy, a widespread degradation system in eukaryotes, plays an important role in maintaining the homeostasis of the cellular environment and the recycling of substances. Optical probes for the tracking of autophagy can be used as an effective tool not only to visualize the autophagy process but also to study autophagy-targeted drugs. Various molecule probes for autophagy of cancer cells emerge but are very limited for that of fungal cells, resulting in the lack of research on antifungal drugs targeting autophagy. To address this issue, we report an azole NIR fluorescence-based theranostic probe with antifungal activity that is sensitive to autophagy-associated pH. The unique design of this probe lies in the introduction of both the pH-sensitive fluorophore with a detection range matching the pH range of the autophagy process and the conserved core structural fragment of azole drugs, providing a strategy to investigate the relationship between antifungal drug action and autophagy. As such, exhibited excellent spectral properties and was found to target and induce the autophagy of the fungal cell membrane while maintaining moderate antifungal activity. Of note, using this theranostic probe as both a dye and drug, the autophagy process of fungi was visualized in a ratiometric manner, revealing the role of azole antifungal drugs in promoting autophagy to induce fungal cell apoptosis.
自噬是真核生物中广泛存在的降解系统，在维持细胞环境的内稳态和物质循环中起着重要作用。自噬追踪的光学探针不仅可以用于可视化自噬过程，还可以用于研究靶向自噬的药物。尽管已经出现了各种用于癌细胞自噬的分子探针，但用于真菌细胞自噬的探针非常有限，导致针对自噬的抗真菌药物研究不足。为了解决这个问题，我们报道了一种具有抗真菌活性的基于唑类近红外荧光的治疗性探针，该探针对与自噬相关的 pH 敏感。该探针的独特设计在于引入了与自噬过程 pH 范围相匹配的检测范围的 pH 敏感荧光团和唑类药物的保守核心结构片段，为研究抗真菌药物作用与自噬之间的关系提供了一种策略。因此，表现出优异的光谱特性，并被发现靶向并诱导真菌细胞膜的自噬，同时保持适度的抗真菌活性。值得注意的是，使用这种治疗性探针作为染料和药物，可以以比率方式可视化真菌的自噬过程，揭示唑类抗真菌药物在促进自噬以诱导真菌细胞凋亡中的作用。
