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

Research output: Contribution to journalArticlepeer-review

Luca Braga, Hashim Ali, Ilaria Secco, Elena Chiavacci, Guilherme Neves, Daniel Goldhill, Rebecca Penn, Jose M. Jimenez-Guardeño, Ana M. Ortega-Prieto, Rossana Bussani, Antonio Cannatà, Giorgia Rizzari, Chiara Collesi, Edoardo Schneider, Daniele Arosio, Ajay M. Shah, Wendy S. Barclay, Michael H. Malim, Juan Burrone, Mauro Giacca

Original languageEnglish
Pages (from-to)88-93
Number of pages6
JournalNature
Volume594
Issue number7861
DOIs
Accepted/In press2021
Published3 Jun 2021

Bibliographical note

Funding Information: Acknowledgements We thank S. Neil, A. Cave, G. Giacca, A. Ivetic and all the other members of the Giacca laboratory who contributed from home during the lockdown period for comments. We acknowledge the generosity of N. Leblanc, K. M. Hoque, M. Hayashi and Iain Greenwood for their gift of reagents and thank M. Guiomar Oliveira for assisting in preparing the cell cultures for electrophysiology. This work was supported by grants from the King’s College London King’s Together programme (to M.G. and M.H.M.); British Heart Foundation (BHF) Programme Grant RG/19/11/34633 (M.G.); King’s College London BHF Centre of Research Excellence grant RE/18/2/34213 (to A.M.S. and M.G.); European Research Council (ERC) Advanced Grant 787971 ‘CuRE’ (to M.G.); Wellcome Trust Investigator Awards (215508/Z/19/Z to J.B. and 106223/Z/14/Z to M.H.M.), BBSRC project grant BB/S000526/1 (J.B.), Huo Family Foundation (M.H.M.), National Institute of Allergy and Infectious Diseases (U54AI150472 and R01AI076119, M.H.M.) and National Institute for Health Research Biomedical Research Centre at Guy’s & St Thomas’ NHS Foundation Trust and King’s College London (IS-BRC-1215-20006, A.M.S., M.H.M. and M.G.). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

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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