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.

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

Rossana Bussani;Chiara Collesi
Investigation
;
Mauro Giacca
2021

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.
7-apr-2021
Pubblicato
https://www.nature.com/articles/s41586-021-03491-6
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/2993737
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