@article{627458c5378c442ba00ede24584d57df,
title = "Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2",
abstract = "There is an urgent need for antivirals to treat the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To identify new candidates, we screen a repurposing library of ∼3,000 drugs. Screening in Vero cells finds few antivirals, while screening in human Huh7.5 cells validates 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we find that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we find nine drugs are antiviral in respiratory cells, seven of which have been used in humans, and three are US Food and Drug Administration (FDA) approved, including cyclosporine. We find that the antiviral activity of cyclosporine is targeting Cyclophilin rather than calcineurin, revealing essential host targets that have the potential for rapid clinical implementation.",
keywords = "antiviral, coronavirus, cyclophilin, cyclosporin, drugs, entry, HTS, SARS2, screening, TMPRSS2",
author = "Mark Dittmar and Lee, {Jae Seung} and Kanupriya Whig and Elisha Segrist and Minghua Li and Brinda Kamalia and Lauren Castellana and Kasirajan Ayyanathan and Cardenas-Diaz, {Fabian L.} and Morrisey, {Edward E.} and Rachel Truitt and Wenli Yang and Kellie Jurado and Kirandeep Samby and Holly Ramage and Schultz, {David C.} and Sara Cherry",
note = "Funding Information: We thank S. Weiss and Y. Li for sharing SARS-Related Coronavirus 2, Isolate USA-WA1/2020 (obtained from the Centers for Disease Control and BEI resources). We thank BEI resources for quantitative SARS-CoV-2 RNA. We thank M. Diamond and S. Hensley for providing anti-Spike antibody (CR3022), C. Coyne for J2 antibody, and M. Diamond for oligo sequences. We thank E. Grice for HaCaT cells. We thank C. Kovacsics for Biosafety support. We thank members of the Cherry lab, members of the High-Throughput Screening Core, David Roth, and John Epstein for discussions. We thank Timothy Wells and Medicines for Malaria Venture for helpful discussions and compounds. We thank the NIH and Mark Foundation (19-011-MIA); Dean's Innovation Fund; Linda and Laddy Montague; BWF; NIAID (5R01AI140539, 1R01AI1502461, and R01AI152362); NCATS, the Fast Grants Award from Mercatus; and the Bill and Melinda Gates Foundation for funding. S.C. is an investigator in the Pathogenesis of Infectious Diseases from the Burroughs Wellcome Fund. D.C.S. and S.C. conceived and oversaw the study. H.R. D.C.S. and S.C. wrote the manuscript. M.D. J.S.L. K.W. E.S. M.L. B.K. L.C. and K.A. performed experiments and analyzed data. F.L.C. E.E.M. R.T. W.Y. K.J. K.S. and H.R. contributed critical expertise, cells, and/or reagents. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = apr,
day = "6",
doi = "10.1016/j.celrep.2021.108959",
language = "English (US)",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}