The news about remdesivir, the investigational anti-viral drug that has shown early promise in the fight against COVID-19, keeps getting better. Researchers at Vanderbilt University Medical Centre (VUMC), the University of North Carolina at Chapel Hill and Gilead Sciences have reported that remdesivir potently inhibited SARS-CoV-2, the virus which causes COVID-19, in human lung cell cultures and that it improved lung function in mice infected with the virus.
These pre-clinical findings help explain the clinical effect the drug has had in treating COVID-19 patients. Remdesivir has been given to patients hospitalised with COVID-19 on a compassionate use basis since late January and through clinical trials since February.
In April, a preliminary report from the multicentre Adaptive COVID-19 Treatment Trial (which included VUMC) suggested that patients who received the drug recovered more quickly.
"All of the results with remdesivir have been very encouraging, even more so than we would have hoped, but it is still investigational, so it was important to directly demonstrate its activity against SARS-CoV-2 in the lab and in an animal model of disease," said VUMC's Dr Andrea Pruijssers.
Pruijssers, research assistant professor of Pediatrics at VUMC and lead antiviral scientist in the laboratory of Dr Mark Denison, is the paper's co-corresponding author with Dr Timothy Sheahan, assistant professor of Epidemiology at UNC-Chapel Hill.
Denison, the EC Stahlman professor of paediatrics at VUMC, directs the division of paediatric infectious diseases. He and Dr Ralph Baric, the William R Kenan, Jr distinguished professor of epidemiology at UNC-Chapel Hill, and colleagues have been studying remdesivir since 2014.
They were the first to perform detailed studies to demonstrate that the drug, which was developed by Gilead Sciences to combat hepatitis C and respiratory syncytial virus, and later the Ebola virus, also showed broad and highly potent activity against coronaviruses in laboratory tests.
The current findings provide "the first rigorous demonstration of potent inhibition of SARS-CoV-2 in continuous and primary human lung cultures." The study is also the first to suggest that remdesivir can block the virus in a mouse model.
Ongoing clinical trials will determine precisely how much it benefits patients in different stages of COVID-19 disease.
Meanwhile in the laboratory, Pruijssers said, "We also are focusing on how to use remdesivir and other drugs in combinations to increase their effectiveness during COVID-19 and to be able to treat at different times of infection."
COVID-19, which to date has infected more than 12m people and killed nearly 600,000 worldwide, is at least the third instance since 2003 in which a coronavirus originally transmitted from bats has caused serious illness in humans.
Thus, there is an urgent need to identify and evaluate broadly efficacious and robust therapies that can limit and prevent coronavirus infections. "Broad-spectrum antiviral drugs, antibodies, and vaccines are needed to combat the current pandemic and those that will emerge in the future," the researchers said.
In addition to SARS-CoV-2, studies in the Denison and Baric labs have shown that remdesivir is effective against a vast array of coronaviruses, including other bat viruses that could emerge in the future in humans.
"We hope that will never happen, but just as we were working to characterize remdesivir over the past six years to be ready for a virus like SARS-CoV-2, we are working and investing now to prepare for any future coronavirus," Denison said. "We want remdesivir and other drugs to be useful both now and in the future."
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the novel viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV) potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). Weaker activity is observed in Vero E6 cells (EC50 = 1.65 μM) due to their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase, of SARS-CoV-2. In mice infected with chimeric virus, therapeutic RDV administration diminishes lung viral load and improves pulmonary function compared to vehicle treated animals. These data demonstrate that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19.
Authors
Andrea J Pruijssers, Amelia S George, Alexandra Schäfer, Sarah R Leist, Lisa E Gralinksi, Kenneth H Dinnon, Boyd L Yount, Maria L Agostini, Laura J Stevens, James D Chappell, Xiaotao Lu, Tia M Hughes, Kendra Gully, David R Martinez, Ariane J Brown, Rachel L Graham, Jason K Perry, Venice Du Pont, Jared Pitts, Bin Ma, Darius Babusis, Eisuke Murakami, Joy Y Feng, John P Bilello, Danielle P Porter, Tomas Cihlar, Ralph S Baric, Mark R Denison, Timothy P Sheahan
[link url="https://www.sciencedaily.com/releases/2020/07/200709172845.htm"]Vanderbilt University Medical Centre[/link]
[link url="https://www.sciencedirect.com/science/article/pii/S2211124720309219"]Cell Reports abstract[/link]