Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine, and Pyronaridine: In Vitro Activity against SARS-CoV-2 and Potential Mechanisms

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  • Puhl, Ana C.
    • Other Affiliation: Collaborations Pharmaceuticals, Inc
  • Fritch, Ethan J.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Lane, Thomas R.
    • Other Affiliation: Collaborations Pharmaceuticals, Inc
  • Tse, Longping V.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Yount, Boyd L.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Sacramento, Carolina Q.
    • Other Affiliation: Instituto Oswaldo Cruz
  • Fintelman-Rodrigues, Natalia
    • Other Affiliation: Instituto Oswaldo Cruz
  • Tavella, Tatyana Almeida
    • Other Affiliation: University of Campinas-UNICAMP
  • Maranhão Costa, Fabio Trindade
    • Other Affiliation: University of Campinas-UNICAMP
  • Weston, Stuart
    • Other Affiliation: University of Maryland School of Medicine
  • Logue, James
    • Other Affiliation: University of Maryland School of Medicine
  • Frieman, Matthew
    • Other Affiliation: University of Maryland School of Medicine
  • Premkumar, Lakshmanane
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Pearce, Kenneth H.
    • Affiliation: Eshelman School of Pharmacy
  • Hurst, Brett L.
    • Other Affiliation: Utah State University
  • Andrade, Carolina Horta
    • Other Affiliation: University of Campinas-UNICAMP
  • Levi, James A.
    • Other Affiliation: North Carolina State University
  • Johnson, Nicole J.
    • Other Affiliation: North Carolina State University
  • Kisthardt, Samantha C.
    • Other Affiliation: North Carolina State University
  • Scholle, Frank
    • Other Affiliation: North Carolina State University
  • Souza, Thiago Moreno L.
    • Other Affiliation: Instituto Oswaldo Cruz
  • Moorman, Nathaniel John
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Baric, Ralph S.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Madrid, Peter B.
    • Other Affiliation: SRI International
  • Ekins, Sean
    • Other Affiliation: Collaborations Pharmaceuticals, Inc
Abstract
  • Severe acute respiratory coronavirus 2 (SARS-CoV-2) is a newly identified virus that has resulted in over 2.5 million deaths globally and over 116 million cases globally in March, 2021. Small-molecule inhibitors that reverse disease severity have proven difficult to discover. One of the key approaches that has been widely applied in an effort to speed up the translation of drugs is drug repurposing. A few drugs have shown in vitro activity against Ebola viruses and demonstrated activity against SARS-CoV-2 in vivo. Most notably, the RNA polymerase targeting remdesivir demonstrated activity in vitro and efficacy in the early stage of the disease in humans. Testing other small-molecule drugs that are active against Ebola viruses (EBOVs) would appear a reasonable strategy to evaluate their potential for SARS-CoV-2. We have previously repurposed pyronaridine, tilorone, and quinacrine (from malaria, influenza, and antiprotozoal uses, respectively) as inhibitors of Ebola and Marburg viruses in vitro in HeLa cells and mouse-adapted EBOV in mice in vivo. We have now tested these three drugs in various cell lines (VeroE6, Vero76, Caco-2, Calu-3, A549-ACE2, HUH-7, and monocytes) infected with SARS-CoV-2 as well as other viruses (including MHV and HCoV 229E). The compilation of these results indicated considerable variability in antiviral activity observed across cell lines. We found that tilorone and pyronaridine inhibited the virus replication in A549-ACE2 cells with IC50 values of 180 nM and IC50 198 nM, respectively. We used microscale thermophoresis to test the binding of these molecules to the spike protein, and tilorone and pyronaridine bind to the spike receptor binding domain protein with Kd values of 339 and 647 nM, respectively. Human Cmax for pyronaridine and quinacrine is greater than the IC50 observed in A549-ACE2 cells. We also provide novel insights into the mechanism of these compounds which is likely lysosomotropic.
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  • Article
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  • In Copyright
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  • Attribution-NonCommercial-NoDerivs 3.0 United States
Journal title
  • ACS Omega
Journal volume
  • 6
Journal issue
  • 11
Page start
  • 7454
Page end
  • 7468
Language
  • English
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  • Publisher
ISSN
  • 2470-1343

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