Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2
Mark Dittmar,
Jae Seung Lee,
Kanupriya Whig,
Elisha Segrist,
Minghua Li,
Brinda Kamalia,
Lauren Castellana,
Kasirajan Ayyanathan,
Fabian L. Cardenas-Diaz,
Edward E. Morrisey,
Rachel Truitt,
Wenli Yang,
Kellie Jurado,
Kirandeep Samby,
Holly Ramage,
David C. Schultz,
Sara Cherry
Affiliations
Mark Dittmar
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Jae Seung Lee
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Kanupriya Whig
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA
Elisha Segrist
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Minghua Li
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Brinda Kamalia
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA
Lauren Castellana
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Kasirajan Ayyanathan
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Fabian L. Cardenas-Diaz
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Edward E. Morrisey
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Rachel Truitt
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Wenli Yang
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Kellie Jurado
Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
Kirandeep Samby
Medicines for Malaria Venture, Geneva, Switzerland
Holly Ramage
Department of Microbiology, Thomas Jefferson University, Philadelphia, PA, USA; Corresponding author
David C. Schultz
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author
Sara Cherry
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author
Summary: 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.
