A campaign targeting a conserved Hsp70 binding site uncovers how subcellular localization is linked to distinct biological activities.
A campaign targeting a conserved Hsp70 binding site uncovers how subcellular localization is linked to distinct biological activities.
复制标题
DOI：
10.1016/j.chembiol.2022.06.006
复制
发表时间：
2022-08-18
影响因子：
8.6
通讯作者：
Frydman, Judith
中科院分区：
文献类型：
--
作者：
Shao, Hao;Taguwa, Shuhei;Gilbert, Luke;Shkedi, Arielle;Sannino, Sara;Guerriero, Christopher J.;Gale-Day, Zachary J.;Young, Zapporah T.;Brodsky, Jeffrey L.;Weissman, Jonathan;Gestwicki, Jason E.;Frydman, Judith
小分子在亚细胞区室中定位的潜力很少被探索。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具有显着不同的分布，其中一些主要存在于线粒体中，而另一些则存在于内质网中。 CRISPRi 筛选支持了这一观点，表明不同的化合物与 ER (HSPA5/BiP) 和线粒体 (HSPA9/mortalin) 的 Hsp70 及其共伴侣具有不同的化学遗传学相互作用。此外，定位似乎甚至可以确定具有保守结合位点的分子的功能。与登革热病毒复制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明显的抗增殖活性，这可能是因为这些过程中需要不同的 Hsp70 组。这些发现强调了亚细胞分配和化学遗传学相互作用对小分子活性的贡献，这些特征在药物化学活动中很少被探索。特定的 Hsp70 子网络可用于治疗不同的疾病，例如癌症和病毒感染，同时最大限度地减少副作用。在这里，Shao 和 Taguwa 等人。通过利用密切相关的 Hsp70 抑制剂的亚细胞分布来应对设计疾病特异性抑制剂的挑战。
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 analogues 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 appeared 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 antiviral 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. Specific targeting of distinct Hsp70 sub-networks could be used to treat different diseases, such as cancer and virus infection while minimizing side effects. Here, Shao and Taguwa et al. address the challenge of designing diseases-specific inhibitors by taking advantage of the sub-cellular distributions of closely related Hsp70 inhibitors.
登录
查看更多内容
影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
DOI：
10.3390/v13030366
发表时间：
2021-02-25
期刊：
Viruses
影响因子：
--
作者：
Etibor TA;Yamauchi Y;Amorim MJ
通讯作者：
Amorim MJ
影响因子：
7.3
作者：
Ambrose, Andrew J.;Chapman, Eli
通讯作者：
Chapman, Eli
影响因子：
2.8
作者：
Frantz, Marie-Celine;Wipf, Peter
通讯作者：
Wipf, Peter
影响因子：
13.8
作者：
Craig EA;Marszalek J
通讯作者：
Marszalek J