RT Journal Article
T1 Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia
A1 Braga, Luca
A1 Ali, Hashim
A1 Secco, Ilaria
A1 Chiavacci, Elena
A1 Neves, Guilherme
A1 Goldhill, Daniel
A1 Penn, Rebecca
A1 Jimenez-Guardeño, Jose Manuel
A1 Ortega-Prieto, Ana María
A1 Bussani, Rossana
A1 Cannata, Antonio
A1 Rizzari, Giorgia
A1 Collesi, Chiara
A1 Scheider, Edoardo
A1 Arosio, Daniele
A1 Ajay M, Shah
A1 Barclay, Wendy S
A1 Malim, Michael H.
A1 Burrone, Juan
A1 Giacca, Mauro
K1 Virología
AB COVID-19 is a disease with unique characteristics that include 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 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.
PB Springer Nature
YR 2021
FD 2021
LK https://hdl.handle.net/10630/33868
UL https://hdl.handle.net/10630/33868
LA eng
NO Braga, L., Ali, H., Secco, I. et al. Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia. Nature 594, 88–93 (2021). https://doi.org/10.1038/s41586-021-03491-6
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 20 ene 2026