A condensate-hardening drug blocks RSV replication in vivo
A condensate-hardening drug blocks RSV replication in vivo
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DOI：
10.1038/s41586-021-03703-z
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发表时间：
2021-07-07
期刊：
影响因子：
64.8
通讯作者：
Altmeyer, Ralf
中科院分区：
文献类型：
--
作者：
Risso-Ballester, Jennifer;Galloux, Marie;Altmeyer, Ralf
生物分子凝聚物已经成为一种重要的亚细胞组织原则（1）。包括人呼吸道合胞病毒（RSV）在内的许多病毒的复制发生在称为包涵体（IB）或病毒质的病毒诱导区室中（2，3）。负链RNA病毒的IB最近被证明是通过相分离形成的生物分子缩合物（4，5）。在这里，我们报告说，甾体生物碱环巴胺及其化学类似物A3 E抑制RSV复制的破坏和硬化IB缩合物。环巴胺和A3 E的作用被RSV转录因子M2-1中的点突变阻断。IB解体发生在几分钟内，这表明这些分子直接作用于IB的液体性质。A3 E和环巴胺抑制感染小鼠肺中的RSV，并且是具有体内活性的冷凝物靶向药物样小分子。我们的数据表明，冷凝物硬化药物不仅可以在病毒复制中对许多以前不可用的靶标进行药理学调节，还可以在癌症驱动超级增强子处对转录因子进行药理学调节（6）。
Biomolecular condensates have emerged as an important subcellular organizing principle(1). Replication of many viruses, including human respiratory syncytial virus (RSV), occurs in virus-induced compartments called inclusion bodies (IBs) or viroplasm(2,3). IBs of negative-strand RNA viruses were recently shown to be biomolecular condensates that form through phase separation(4,5). Here we report that the steroidal alkaloid cyclopamine and its chemical analogue A3E inhibit RSV replication by disorganizing and hardening IB condensates. The actions of cyclopamine and A3E were blocked by a point mutation in the RSV transcription factor M2-1. IB disorganization occurred within minutes, which suggests that these molecules directly act on the liquid properties of the IBs. A3E and cyclopamine inhibit RSV in the lungs of infected mice and are condensate-targeting drug-like small molecules that have in vivo activity. Our data show that condensate-hardening drugs may enable the pharmacological modulation of not only many previously undruggable targets in viral replication but also transcription factors at cancer-driving super-enhancers(6).