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Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia.
- Source :
-
Nature [Nature] 2021 Jun; Vol. 594 (7861), pp. 88-93. Date of Electronic Publication: 2021 Apr 07. - Publication Year :
- 2021
-
Abstract
- COVID-19 is a disease with unique characteristics that include lung thrombosis <superscript>1</superscript> , frequent diarrhoea <superscript>2</superscript> , abnormal activation of the inflammatory response <superscript>3</superscript> and rapid deterioration of lung function consistent with alveolar oedema <superscript>4</superscript> . 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.
- Subjects :
- Aged
Aged, 80 and over
Alveolar Epithelial Cells drug effects
Alveolar Epithelial Cells pathology
Alveolar Epithelial Cells virology
Animals
Anoctamins metabolism
COVID-19 metabolism
COVID-19 virology
Calcium Signaling drug effects
Cell Line
Chloride Channels metabolism
Chlorocebus aethiops
Female
Giant Cells metabolism
Giant Cells virology
Humans
Lung drug effects
Lung pathology
Lung virology
Male
SARS-CoV-2 metabolism
SARS-CoV-2 pathogenicity
Spike Glycoprotein, Coronavirus metabolism
Virus Replication drug effects
Anoctamins antagonists & inhibitors
COVID-19 pathology
Cell Fusion
Drug Evaluation, Preclinical
Giant Cells drug effects
SARS-CoV-2 drug effects
Spike Glycoprotein, Coronavirus antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 594
- Issue :
- 7861
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 33827113
- Full Text :
- https://doi.org/10.1038/s41586-021-03491-6