Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells
Adam Pickard , Ben C. Calverley, Joan Chang, Richa Garva, Sara Gago, Yinhui Lu, Karl E. Kadler
Abstract:
While COVID-19 vaccines targeting the Spike protein of SARS-CoV-2 have demonstrated efficacy in preventing infection, there is still a need for therapeutics to manage the disease until global immunity is achieved. The identification of repurposed drugs that can halt SARS-CoV-2 replication would be highly beneficial in controlling the spread of the disease.
Introduction:
The SARS-CoV-2 virus, responsible for the COVID-19 pandemic, has had a significant impact on global health, resulting in substantial loss of life. In COVID-19 patients, SARS-CoV-2 infection can lead to pulmonary distress, inflammation, and affect multiple organs.
Materials and methods:
To generate functional SARS-CoV-2 virus, DNA encoding the viral genome and SARS-CoV-2-ΔOrf7a-NLuc were obtained. Attempts to produce replicative virus by transfecting the DNA into 293T cells were unsuccessful. Virus production, maintenance, and titer assessment were performed using collected culture medium and Vero cells. Electron microscopy was conducted after infecting Vero cells with the P4 virus. NLuc activity assay was used to assess NLuc activity in infected Vero cells. Drug screens were performed using the DiscoveryProbe FDA-approved library of 1971 compounds.
Discussion:
This study demonstrated that the SARS-CoV-2 virus can infect and replicate in various human cells, particularly hepatocytes, kidney glomerulus, and proximal tubule cells of the kidney. Furthermore, it identified nine drugs that have been approved by the FDA for clinical use and have shown efficacy in inhibiting SARS-CoV-2 replication even after infection. These drugs have a proven safety profile in humans, making them potential candidates for COVID-19 treatment.
Acknowledgments: The authors thank Dr. Jennifer Cavet for providing assistance with working at containing level 3 and use of the facilities.
Citation: Pickard A, Calverley BC, Chang J, Garva R, Gago S, Lu Y, et al. (2021) Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells. PLoS Pathog 17(9): e1009840. https://doi.org/10.1371/journal.ppat.1009840
Editor: Andrew Pekosz, Johns Hopkins University Bloomberg School of Public Health, UNITED STATES
Received: May 27, 2021; Accepted: July 26, 2021; Published: September 9, 2021.
Copyright: © 2021 Pickard et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The research was funded by Wellcome (London) (110126/Z/15/Z and 203128/Z/16/Z) to KEK. SG was funded by the NIHR Manchester Research Centre and the Fungal Infection Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
