Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia.
Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia.
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DOI：
10.1038/s41586-021-03491-6
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发表时间：
2021-06
期刊：
影响因子：
64.8
通讯作者：
Giacca M
中科院分区：
文献类型：
--
作者：
Braga L;Ali H;Secco I;Chiavacci E;Neves G;Goldhill D;Penn R;Jimenez-Guardeño JM;Ortega-Prieto AM;Bussani R;Cannatà A;Rizzari G;Collesi C;Schneider E;Arosio D;Shah AM;Barclay WS;Malim MH;Burrone J;Giacca M
COVID-19是一种具有独特特征的疾病，包括肺血栓形成、频繁腹泻、炎症反应异常激活以及与肺泡水肿一致的肺功能迅速恶化。这些发现的病理基础仍然难以捉摸。我们发现，COVID-19患者的肺部含有感染的肺细胞，形态异常，多核频繁。这些合胞体的产生是在细胞膜水平上激活SARS-CoV-2刺突蛋白的结果。基于这些观察结果，我们对超过3000种批准的药物进行了两次高含量的显微镜筛选，以寻找spike驱动合胞体的抑制剂。我们鉴定了83种抑制spike介导的细胞融合的药物，其中一些属于确定的药理学类别。我们把注意力集中在有效的药物上，这些药物也可以防止病毒复制和相关的细胞病变。其中最有效的分子之一是氯硝柳胺，它通过抑制TMEMI6F/Anoctamin6（一种钙活化离子通道和负责细胞表面磷脂酰丝氨酸暴露的超扰酶）的活性，显著地减弱了钙振荡和膜电导。这些发现提示了COVID-19疾病发病机制的潜在机制，并支持将氯硝柳胺重新用于治疗。
COVID-19 is a disease with unique characteristics including lung thrombosis , frequent diarrhoea , abnormal activation of the inflammatory response and rapid deterioration of lung function consistent with alveolar oedema. The pathological substrate for these findings remains elusive. Here we show that the lungs of patients with COVID-19 contain infected pneumocytes with abnormal morphology and frequent multinucleation. Generation of these syncytia results from activation of the SARS-CoV-2 Spike protein at the cell plasma membrane level. Based on these observations, we performed two high-content microscopy-based screenings with over 3000 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 focussed our attention on effective drugs that also protected against virus replication and associated cytopathicity. One of the most effective molecules was Niclosamide, which markedly blunted calcium oscillations and membrane conductances in Spike-expressing cells by suppressing the activity of TMEMI6F/Anoctamin6, a calcium-activated ion channel and scramblase responsible for phosphatidylserine exposure on the cell surface. These findings suggest a potential mechanism for COVID-19 disease pathogenesis and support the repurposing of Niclosamide for therapy.
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影响因子：
7.3
作者：
Jin X;Shah S;Liu Y;Zhang H;Lees M;Fu Z;Lippiat JD;Beech DJ;Sivaprasadarao A;Baldwin SA;Zhang H;Gamper N
通讯作者：
Gamper N
影响因子：
5.4
作者：
Glowacka, Ilona;Bertram, Stephanie;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan
影响因子：
8.9
作者：
Kappagoda, Shanthi;Singh, Upinder;Blackburn, Brian G.
通讯作者：
Blackburn, Brian G.
影响因子：
2.1
作者：
Edler, Carolin;Schroeder, Ann Sophie;Sperhake, Jan-Peter
通讯作者：
Sperhake, Jan-Peter
DOI：
10.1007/978-3-319-75474-1_4
发表时间：
2018-02-16
期刊：
Activation of Viruses by Host Proteases
影响因子：
--
作者：
Hoffmann M;Hofmann-Winkler H;Pöhlmann S
通讯作者：
Pöhlmann S