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Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia
Nature ( IF 50.5 ) Pub Date : 2021-04-07 , DOI: 10.1038/s41586-021-03491-6
Luca Braga 1 , Hashim Ali 1 , Ilaria Secco 1 , Elena Chiavacci 1 , Guilherme Neves 2, 3 , Daniel Goldhill 4 , Rebecca Penn 4 , Jose M Jimenez-Guardeño 5 , Ana M Ortega-Prieto 5 , Rossana Bussani 6 , Antonio Cannatà 1 , Giorgia Rizzari 1 , Chiara Collesi 6, 7 , Edoardo Schneider 1, 7 , Daniele Arosio 8 , Ajay M Shah 1 , Wendy S Barclay 4 , Michael H Malim 5 , Juan Burrone 2, 3 , Mauro Giacca 1, 6, 7
Affiliation  

COVID-19 is a disease with unique characteristics that include lung thrombosis1, frequent diarrhoea2, abnormal activation of the inflammatory response3 and rapid deterioration of lung function consistent with alveolar oedema4. The pathological substrate for these findings remains unknown. Here we show that the lungs of patients with COVID-19 contain infected pneumocytes with abnormal morphology and frequent multinucleation. The generation of these syncytia results from activation of the SARS-CoV-2 spike protein at the cell plasma membrane level. On the basis of these observations, we performed two high-content microscopy-based screenings with more than 3,000 approved drugs to search for inhibitors of spike-driven syncytia. We converged on the identification of 83 drugs that inhibited spike-mediated cell fusion, several of which belonged to defined pharmacological classes. We focused our attention on effective drugs that also protected against virus replication and associated cytopathicity. One of the most effective molecules was the antihelminthic drug niclosamide, which markedly blunted calcium oscillations and membrane conductance in spike-expressing cells by suppressing the activity of TMEM16F (also known as anoctamin 6), a calcium-activated ion channel and scramblase that is responsible for exposure of phosphatidylserine on the cell surface. These findings suggest a potential mechanism for COVID-19 disease pathogenesis and support the repurposing of niclosamide for therapy.



中文翻译:


抑制 TMEM16 蛋白的药物可阻断 SARS-CoV-2 刺突诱导的合胞体



COVID-19 是一种具有独特特征的疾病,包括肺血栓形成1 、频繁腹泻2 、炎症反应异常激活3以及与肺泡水肿一致的肺功能快速恶化4 。这些发现的病理基础仍然未知。在这里,我们发现 COVID-19 患者的肺部含有形态异常且频繁出现多核的受感染肺细胞。这些合胞体的产生是由于细胞质膜水平上 SARS-CoV-2 刺突蛋白的激活所致。根据这些观察结果,我们对 3,000 多种批准的药物进行了两次基于显微镜的高内涵筛选,以寻找刺突驱动合胞体的抑制剂。我们集中鉴定了 83 种抑制刺突介导的细胞融合的药物,其中一些药物属于特定的药理学类别。我们将注意力集中在能够防止病毒复制和相关细胞病变的有效药物上。最有效的分子之一是抗蠕虫药物氯硝柳胺,它通过抑制 TMEM16F(也称为 anoctamin 6)的活性,显着减弱尖峰表达细胞中的钙振荡和膜电导,TMEM16F 是一种钙激活离子通道和扰乱酶,负责调节用于将磷脂酰丝氨酸暴露在细胞表面。这些发现提示了 COVID-19 疾病发病机制的潜在机制,并支持重新利用氯硝柳胺进行治疗。

更新日期:2021-04-07
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