Journal
NATURE
Volume 594, Issue 7861, Pages 88-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03491-6
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Funding
- King's College London King's Together programme
- British Heart Foundation (BHF) [RG/19/11/34633]
- King's College London BHF Centre of Research Excellence [RE/18/2/34213]
- European Research Council (ERC) [787971]
- Wellcome Trust Investigator Awards [215508/Z/19/Z, 106223/Z/14/Z]
- BBSRC [BB/S000526/1]
- Huo Family Foundation
- National Institute of Allergy and Infectious Diseases [U54AI150472, R01AI076119]
- National Institute for Health Research Biomedical Research Centre at Guy's AMP
- St Thomas' NHS Foundation Trust and King's College London [IS-BRC-1215-20006]
- Wellcome Trust [215508/Z/19/Z, 106223/Z/14/Z] Funding Source: Wellcome Trust
- BBSRC [BB/S000526/1] Funding Source: UKRI
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COVID-19 patients' lungs contain infected pneumocytes with abnormal morphology and frequent multinucleation, leading to the formation of syncytia driven by the activation of the SARS-CoV-2 spike protein. The antihelminthic drug niclosamide has shown to effectively inhibit cell fusion, potentially providing a new therapeutic approach for COVID-19 disease pathogenesis.
COVID-19 is a disease with unique characteristics that include lung thrombosis(1), frequent diarrhoea(2), abnormal activation of the inflammatory response(3) and rapid deterioration of lung function consistent with alveolar oedema(4). 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.
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