Abstract: PLOS PATHOGENS RESEARCH ARTICLE Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells Adam Pickard ID1,2*, Ben C. Calverley ID1,2, Joan Chang ID1,2, Richa Garva ID1,2, Sara Gago2, Yinhui Lu1,2, Karl E. Kadler ID1,2* 1 Wellcome Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester, United Kingdom, 2 School of Biological Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom * adam.pickard@manchester.ac.uk (AP); karl.kadler@manchester.ac.uk (KEK) a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Pickard A, Calverley BC, Chang J, Garva R, Gago S, Lu Y, et al. (2021) Discovery of repurposed 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 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.ppat.1009840 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 Statement: All relevant data are within the manuscript and its Supporting Information files. Abstract COVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, therapeutics that can help manage the disease are still required until immunity has been achieved globally. The identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARSCoV-2-ΔOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in-line with reported proteinuria and liver damage in patients with COVID-19. Using the nano-luciferase as a measure of virus replication we identified 35 drugs that reduced replication in Vero cells and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID. Author summary The identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming COVID-19. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2-ΔOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their..