Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Purdue Institute for Drug Discovery, West Lafayette, IN 47907, USA.
Chembiochem. 2022 May 4;23(9):e202100378. doi: 10.1002/cbic.202100378. Epub 2021 Oct 13.
Targeting live cell organelles is essential for imaging, understanding, and controlling specific biochemical processes. Typically, fluorescent probes with distinct structural scaffolds are used to target specific cell organelles. Here, we have designed a modular one-step synthetic strategy using a common reaction intermediate to develop new lysosomal, mitochondrial, and nucleus-targeting pH-activable fluorescent probes that are all based on a single boron dipyrromethane scaffold. The divergent cell organelle targeting was achieved by synthesizing probes with specific functional group changes to the central scaffold resulting in differential fluorescence and pK . Specifically, we show that the functional group transformation of the same scaffold influences cellular localization and specificity of pH-activable fluorescent probes in live primary microglial cells with pK values ranging from ∼3.2-6.0. We introduce a structure-organelle-relationship (SOR) framework to target nuclei (NucShine), lysosomes (LysoShine), and mitochondria (MitoShine) in live microglia. This work will result in future applications of SOR beyond imaging to target and control organelle-specific biochemical processes in disease-specific models.
靶向活细胞细胞器对于成像、理解和控制特定生化过程至关重要。通常，使用具有独特结构支架的荧光探针来靶向特定的细胞细胞器。在这里，我们设计了一种使用通用反应中间体的模块化一步合成策略，开发了基于单个硼二吡咯甲烷支架的新型溶酶体、线粒体和核靶向 pH 激活荧光探针。通过对中心支架进行特定的官能团改变来合成探针，从而实现了不同的细胞细胞器靶向，这导致了荧光和 pK 的差异。具体来说，我们表明，同一支架的官能团转化会影响具有约 3.2-6.0 的 pK 值的活原代小神经胶质细胞中 pH 激活荧光探针的细胞定位和特异性。我们引入了一种结构-细胞器关系 (SOR) 框架，以在活小神经胶质细胞中靶向细胞核 (NucShine)、溶酶体 (LysoShine) 和线粒体 (MitoShine)。这项工作将导致 SOR 在成像之外的未来应用，以在疾病特异性模型中靶向和控制细胞器特异性生化过程。
