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Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia

Nature (London), 2021-06, Vol.594 (7861), p.88-93 [Peer Reviewed Journal]

Copyright Nature Publishing Group Jun 3, 2021 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/s41586-021-03491-6 ;PMID: 33827113

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Title:
Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia
Author: Braga, Luca ; Ali, Hashim ; Secco, Ilaria ; Chiavacci, Elena ; Neves, Guilherme ; Goldhill, Daniel ; Penn, Rebecca ; Jimenez-Guardeño, Jose M ; Ortega-Prieto, Ana M ; Bussani, Rossana ; Cannatà, Antonio ; Rizzari, Giorgia ; Collesi, Chiara ; Schneider, Edoardo ; Arosio, Daniele ; Shah, Ajay M ; Barclay, Wendy S ; Malim, Michael H ; Burrone, Juan ; Giacca, Mauro
Subjects: Aged ; Aged, 80 and over ; Alveolar Epithelial Cells - drug effects ; Alveolar Epithelial Cells - pathology ; Alveolar Epithelial Cells - virology ; Alveoli ; Animals ; Anoctamins - antagonists & inhibitors ; Anoctamins - metabolism ; Anthelmintic agents ; Calcium ; Calcium conductance ; Calcium Signaling - drug effects ; Calcium signalling ; Cell Fusion ; Cell Line ; Cell surface ; Chloride Channels - metabolism ; Chlorocebus aethiops ; Coronaviruses ; COVID-19 ; COVID-19 - metabolism ; COVID-19 - pathology ; COVID-19 - virology ; Drug dosages ; Drug Evaluation, Preclinical ; Drugs ; Female ; Giant Cells - drug effects ; Giant Cells - metabolism ; Giant Cells - virology ; Humans ; Inflammation ; Ion channels ; Lung - drug effects ; Lung - pathology ; Lung - virology ; Lungs ; Male ; Membrane conductance ; Membranes ; Middle East respiratory syndrome ; Morphology ; Niclosamide ; Oscillations ; Pathogenesis ; Phosphatidylserine ; Plasma ; Pneumocytes ; Proteins ; Respiratory function ; SARS-CoV-2 - drug effects ; SARS-CoV-2 - metabolism ; SARS-CoV-2 - pathogenicity ; Severe acute respiratory syndrome ; Severe acute respiratory syndrome coronavirus 2 ; Spike Glycoprotein, Coronavirus - antagonists & inhibitors ; Spike Glycoprotein, Coronavirus - metabolism ; Spike protein ; Substrates ; Syncytia ; Viral diseases ; Virus Replication - drug effects ; Viruses
Is Part Of: Nature (London), 2021-06, Vol.594 (7861), p.88-93
Description: COVID-19 is a disease with unique characteristics that include 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 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.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 0028-0836
EISSN: 1476-4687
DOI: 10.1038/s41586-021-03491-6
PMID: 33827113
Source: ProQuest One Psychology
MEDLINE
ProQuest Central

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Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia

Copyright Nature Publishing Group Jun 3, 2021 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/s41586-021-03491-6 ;PMID: 33827113

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