小柯机器人

2021年4月7日，《自然》杂志在线发表了英国科学家的一项最新研究成果。来自伦敦国王学院的Mauro Giacca研究团队发现，抑制TMEM16蛋白的药物可阻断SARS-CoV-2突刺诱导的合胞体。

研究人员发现，COVID-19患者的肺中含有感染的肺细胞，它们具有异常的形态和频繁的多核化作用。这些合胞体的产生是由于SARS-CoV-2突刺蛋白在细胞质膜水平上的激活所致。基于这些观察结果，研究人员对超过3000种已批准的药物进行了两次高倍镜检，以寻找突刺驱动合胞体的抑制剂。研究人员集中于鉴定抑制突刺介导细胞融合的83种药物，其中几种属于已定义的药理学类别。研究人员也将注意力集中在还可以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Niclosamide，它可以通过抑制TMEM16F/Anoctamin6（钙激活的离子通道和scramblase的活性，使细胞表面磷脂酰丝氨酸的暴露）显著减弱突刺表达细胞中的钙振荡和膜电导。这些发现提示了COVID-19疾病发病机制的潜在机制，并支持重新使用Niclosamide进行治疗。 

据了解，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、炎症反应异常激活和与肺泡水肿相一致的肺功能快速恶化。这些发现的病理基础仍然难以捉摸。

附：英文原文

Title: Drugs that inhibit TMEM16 proteins block SARS-CoV-2 Spike-induced syncytia

Author: Luca Braga, Hashim Ali, Ilaria Secco, Elena Chiavacci, Guilherme Neves, Daniel Goldhill, Rebecca Penn, Jose M. Jimenez-Guardeo, Ana M. Ortega-Prieto, Rossana Bussani, Antonio Cannat, Giorgia Rizzari, Chiara Collesi, Edoardo Schneider, Daniele Arosio, Ajay M. Shah, Wendy S. Barclay, Michael H. Malim, Juan Burrone, Mauro Giacca

Issue&Volume: 2021-04-07

Abstract: COVID-19 is a disease with unique characteristics including 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 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 TMEM16F/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.

DOI: 10.1038/s41586-021-03491-6

Source: https://www.nature.com/articles/s41586-021-03491-6

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