Department of Chemistry and Biochemistry, Institute of Molecular Biology, Knight Campus for Accelerating Scientific Impact, Materials Science Institute, University of Oregon, Eugene, Oregon 97403, United States.
J Am Chem Soc. 2022 Sep 28;144(38):17651-17660. doi: 10.1021/jacs.2c07225. Epub 2022 Sep 19.
Hydrogen sulfide (HS) is an endogenously produced gaseous signaling molecule with important roles in regulating organelle function and stress. Because of its high reactivity, targeted delivery of HS using small molecule HS donors has garnered significant interest to minimize off-target effects. Although mitochondrially targeted HS donors, such as AP39, have been reported previously and exhibit significantly higher potency than nontargeted donors, the expansion of targeted HS delivery to other subcellular organelles remains largely absent. To fill this key unmet need, we report a library of organelle-targeted HS donors that localize HS delivery to specific subcellular organelles, including the Golgi apparatus, lysosome, endoplasmic reticulum, and mitochondria. We measured HS production in vitro from each donor, confirmed the localization of HS delivery using organelle-specific HS responsive fluorescent probes, and demonstrated enhanced potency of these targeted HS donors in providing protection against organelle-specific stress. We anticipate this class of targeted HS donors will enable future studies of subcellular roles of HS and the pathways by which HS alleviates subcellular organelle stress.
硫化氢 (HS) 是一种内源性产生的气体信号分子，在调节细胞器功能和应激方面具有重要作用。由于其高反应性，使用小分子 HS 供体靶向递送 HS 引起了人们的极大兴趣，以尽量减少脱靶效应。尽管先前已经报道了靶向于线粒体的 HS 供体，如 AP39，并且比非靶向供体具有显著更高的效力，但将靶向 HS 递送至其他亚细胞器的应用仍然很大程度上尚未实现。为了满足这一关键的未满足需求，我们报告了一组靶向于细胞器的 HS 供体库，这些供体将 HS 递送至特定的亚细胞器，包括高尔基体、溶酶体、内质网和线粒体。我们从每个供体中测量了 HS 的体外产生，使用细胞器特异性 HS 响应荧光探针证实了 HS 递送的定位，并证明了这些靶向 HS 供体在提供针对细胞器特异性应激的保护方面的增强效力。我们预计，这类靶向 HS 供体将能够促进未来对 HS 在亚细胞水平上的作用以及 HS 缓解亚细胞器应激的途径的研究。
