2. Academic Validation
  3. Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2

Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2

  • Cell Rep. 2021 Apr 6;35(1):108959. doi: 10.1016/j.celrep.2021.108959.
Mark Dittmar 1,  Jae Seung Lee 1,  Kanupriya Whig 2,  Elisha Segrist 1,  Minghua Li 1,  Brinda Kamalia 2,  Lauren Castellana 1,  Kasirajan Ayyanathan 1,  Fabian L Cardenas-Diaz 3,  Edward E Morrisey 3,  Rachel Truitt 3,  Wenli Yang 3,  Kellie Jurado 4,  Kirandeep Samby 5,  Holly Ramage 6,  David C Schultz 7,  Sara Cherry 8
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA.
  • 3 Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Medicines for Malaria Venture, Geneva, Switzerland.
  • 6 Department of Microbiology, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: [email protected].
  • 7 Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: [email protected].
  • 8 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. Electronic address: [email protected].
PMID: 33811811 DOI: 10.1016/j.celrep.2021.108959
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

HTS; SARS2; TMPRSS2; antiviral; coronavirus; cyclophilin; cyclosporin; drugs; entry; screening.

Figures
Products