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

Autor: Braga L; King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK., Ali H; King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK., Secco I; King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK., Chiavacci E; King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK., Neves G; MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.; Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Goldhill D; Department of Infectious Diseases, Imperial College London, London, UK., Penn R; Department of Infectious Diseases, Imperial College London, London, UK., Jimenez-Guardeño JM; Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK., Ortega-Prieto AM; Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK., Bussani R; Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy., Cannatà A; King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK., Rizzari G; King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK., Collesi C; Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.; International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy., Schneider E; King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK.; International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy., Arosio D; Istituto di Biofisica (IBF), Consiglio Nazionale delle Ricerche (CNR), Trento, Italy., Shah AM; King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK., Barclay WS; Department of Infectious Diseases, Imperial College London, London, UK., Malim MH; Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK., Burrone J; MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.; Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Giacca M; King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK. mauro.giacca@kcl.ac.uk.; Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy. mauro.giacca@kcl.ac.uk.; International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy. mauro.giacca@kcl.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Jun; Vol. 594 (7861), pp. 88-93. Date of Electronic Publication: 2021 Apr 07.
DOI: 10.1038/s41586-021-03491-6
Abstrakt: 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.
Databáze: MEDLINE
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