A drug that is commonly used to treat tapeworm infections might help to prevent the formation of atypical fused cells in the lungs of patients with COVID-19, according to laboratory experiments.
Niclosamide was originally developed in the 1950s as a molluscicide against snails. It was later approved for use against tapeworm infections in humans and is already known to be active against various viruses, including SARS-CoV-2.
Mauro Giacca and colleagues at King’s College London, studied post-mortem samples from the lungs of 41 patients who had died from COVID-19 between March and May 2020, and found that the tissue often contains lung epithelial cells that have become fused together. Some of these fused cells, known as syncytia, contain over 20 different nuclei. The authors found that this fusion process is mediated by the spike protein of SARS-CoV-2, which triggers calcium oscillations and the activation of a protein called TMEM16F.
On the basis of these observations, the authors screened over 3,000 clinically approved drugs to look for molecules that block this spike-driven fusion of cells. The screen identified 83 drugs, and further experiments focused on 43 molecules that also protected against viral replication and cell damage.
Of these, one of the most effective molecules was the anti-parasitic drug niclosamide.
This drug was found to inhibit viral replication, blunt calcium oscillation in spike-expressing cells, suppress the activity of TMEM16F and prevent the formation of spike-induced syncytia in laboratory tests. The authors note that other drugs that are known to inhibit members of the TMEM16 family of proteins also performed well in their tests and could warrant further investigation as treatments for COVID-19.
Study details
Drugs that inhibit TMEM16 proteins block SARS-CoV-2 Spike-induced syncytia
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
Published in Nature on 7 April 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.