小柯机器人

药物破坏相分离可阻断RSV在体内的复制
2021-07-08 17:47

香港大学Ralf Altmeyer、法国巴黎-萨克雷大学Marie-Anne Rameix-Welti和Marie-Anne Rameix-Welti研究组合作发现,药物破坏凝聚物可在体内阻断人类呼吸道合胞病毒 (RSV) 的复制。该研究于2021年7月7日发表于国际学术期刊《自然》杂志。

在本研究中,研究人员发现甾体生物碱环巴胺及其化学类似物A3E通过破坏和硬化包涵体 (IB)凝聚物来抑制RSV复制。RSV转录因子M2-1的点突变可阻断环巴胺和A3E的作用。IB 在几分钟内发生解体,这表明这些分子直接作用于IB的液相。A3E和环巴胺能抑制受感染小鼠肺中的RSV,可作为具有体内活性的凝聚物靶向药物小分子。

该数据表明,凝聚物硬化药物不仅可以靶向病毒复制中许多先前无法成药的靶点,还可以对促进癌症发生超级增强子的转录因子进行药理学调节。

据介绍,生物分子凝聚物已成为重要的亚细胞组织方式。许多病毒的复制发生在被称为包涵体 (IB) 或病毒质的病毒诱导区室中,例如RSV。最近的研究表明反义链RNA病毒的IB可通过相分离形成生物分子凝聚物。

附:英文原文

Title: A condensate-hardening drug blocks RSV replication in vivo

Author: Jennifer Risso-Ballester, Marie Galloux, Jingjing Cao, Ronan Le Goffic, Fortune Hontonnou, Aude Jobart-Malfait, Aurore Desquesnes, Svenja M. Sake, Sibylle Haid, Miaomiao Du, Xiumei Zhang, Huanyun Zhang, Zhaoguo Wang, Vincent Rincheval, Youming Zhang, Thomas Pietschmann, Jean-Franois Elout, Marie-Anne Rameix-Welti, Ralf Altmeyer

Issue&Volume: 2021-07-07

Abstract: Biomolecular condensates have emerged as an important subcellular organizing principle1. Replication of many viruses, including human respiratory syncytial virus (RSV), occurs in virus-induced compartments called inclusion bodies (IBs) or viroplasm2,3. IBs of negative-strand RNA viruses were recently shown to be biomolecular condensates that form through phase separation4,5. 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-enhancers6.

DOI: 10.1038/s41586-021-03703-z

Source: https://www.nature.com/articles/s41586-021-03703-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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