PDF(Pubmed)
Abstract：
The potential of small molecules to localize within subcellular compartments is rarely explored. To probe this question, we measured the localization of Hsp70 inhibitors using fluorescence microscopy. We found that even closely related analogs had dramatically different distributions, with some residing predominantly in the mitochondria and others in the ER. CRISPRi screens supported this idea, showing that different compounds had distinct chemogenetic interactions with Hsp70s of the ER (HSPA5/BiP) and mitochondria (HSPA9/mortalin) and their co-chaperones. Moreover, localization seemed to determine function, even for molecules with conserved binding sites. Compounds with distinct partitioning have distinct anti-proliferative activity in breast cancer cells compared with anti-viral activity in cellular models of Dengue virus replication, likely because different sets of Hsp70s are required in these processes. These findings highlight the contributions of subcellular partitioning and chemogenetic interactions to small molecule activity, features that are rarely explored during medicinal chemistry campaigns.
摘要：
很少探索小分子定位在亚细胞区室中的潜力。为了探究这个问题，我们使用荧光显微镜测量了Hsp70抑制剂的定位。我们发现即使是密切相关的类似物也有明显不同的分布，其中一些主要存在于线粒体中，另一些主要存在于ER中。CRISPRi屏幕支持这个想法，表明不同的化合物与ER（HSPA5/BiP）的Hsp70s和线粒体（HSPA9/mortalin）及其共同伴侣具有不同的化学遗传相互作用。此外，本地化似乎决定了功能，甚至对于具有保守结合位点的分子。与登革病毒复制的细胞模型中的抗病毒活性相比，具有不同分配的化合物在乳腺癌细胞中具有不同的抗增殖活性。可能是因为在这些过程中需要不同的Hsp70。这些发现强调了亚细胞分配和化学遗传相互作用对小分子活性的贡献，在药物化学运动中很少探索的功能。
