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REPURPOSING THE EBOLA AND MARBURG VIRUS INHIBITORS TILORONE, QUINACRINE, AND PYRONARIDINE: IN VITRO ACTIVITY AGAINST SARS-COV‑2 AND POTENTIAL MECHANISMS
Puhl, A. C. et al. | Date Issued: 2021
Author
Puhl, A. C.
Fritch, Ethan J.
Lane, Thomas R.
Tse, Longping Victor
Yount, Boyd L.
Sacramento, Carolina Q.
Fintelman-Rodrigues, Natalia
Tavella, Tatyana Almeida
Costa, Fabio Trindade Maranhão
Weston, Stuart
Logue, James
Frieman, Matthew
Premkumar, Lakshmanane
Pearce, Kenneth H.
Hurst, Brett L.
Andrade, Carolina Horta
Levi, James A.
Johnson, Nicole J.
Kisthardt, Samantha C.
Scholle, Frank
Souza, Thiago Moreno L.
Moorman, Nathaniel John
Baric, Ralph S.
Madrid, Peter B.
Ekins, Sean
Affilliation
Collaborations Pharmaceuticals, Inc., Raleigh. North Carolina 27606, USA.
Collaborations Pharmaceuticals, Inc., Raleigh. North Carolina 27606, USA.
University of North Carolina School of Medicine. Department of Microbiology and Immunology. Chapel Hill, North Carolina 27599, USA.
Collaborations Pharmaceuticals, Inc., Raleigh. North Carolina 27606, USA.
University of North Carolina School of Medicine. Department of Epidemiology, Chapel Hill, North Carolina. 27599, USA.
University of North Carolina School of Medicine. Department of Epidemiology, Chapel Hill, North Carolina. 27599, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde (CDTS). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde (CDTS). Rio de Janeiro, RJ, Brasil.
Universidade de Campinas. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Prof. Dr. Luiz Jacinto da Silva. Campinas, SP, Brasil.
Universidade de Campinas. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Prof. Dr. Luiz Jacinto da Silva. Campinas, SP, Brasil.
University of Maryland School of Medicine. Department of Microbiology and Immunology. Maryland, 21201, USA.
University of Maryland School of Medicine. Department of Microbiology and Immunology. Maryland, 21201, USA.
University of Maryland School of Medicine. Department of Microbiology and Immunology. Baltimore, Maryland 21201,
University of North Carolina School of Medicine. Department of Microbiology and Immunology. Chape HIll, North Carolina, USA.
Center for Integrative Chemical Biology and Drug Discovery. Chemical Biology and Medicinal Chemistry. Eshelman School of Pharmacy. University of North Carolina, Chapel Hill, North Carolina 27599, United States; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599,USA.
Institute for Antiviral Research, Utah State University, Logan, Utah 84322, United States; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah 84322, USA.
University of Campinas-UNICAMP. Departamento de Genética, Evolução Microbiologia e Imunologia. Laboratório de Doenças Tropical Prof. Dr. Luiz Jacinto da Silva. Campinas, SP, Brasil / Universidade Federal de Goiás. Faculdade de Farmácia. abMolLaboratório de Modelagem Molecular e Projteo. Fármaco. Goiânia, GO, Brasil.
North Carolina State University. Department of Biological Sciences. Raleigh, North Carolina 27695. USA.
North Carolina State University. Department of Biological Sciences. Raleigh, North Carolina 27695. USA.
North Carolina State University. Department of Biological Sciences. Raleigh, North Carolina 27695. USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde (CDTS). Rio de Janeiro, RJ, Brasil.
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA / Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA / Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Department of Microbiology and Immunology and Department of Epidemiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA / Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , USA.
SRI International. Menlo Park, California 94025, USA.
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.
Keywords in Portuguese
Vitro Activity against SARS-CoV‑2
Reaproveitando
Inibidores do vírus Ebola e Marburg Tilorone
Quinacrina e Pironaridina
Mecanismos Potenciais
 
Keywords
Atividade In Vitro contra SARS-CoV‑2
Repurposing
Ebola and Marburg Virus
Inhibitors Tilorone, Quinacrine, and Pyronaridine
Potential Mechanisms
 
Publisher
ACS Publications
Citation
PUHL, Ana C. et al. Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine, and Pyronaridine: In Vitro Activity against SARS-CoV‑2 and Potential Mechanisms. ACS OMEGA, v. 6, p. 7454-7468, Mar. 2021.
Previous version
https://www.arca.fiocruz.br/handle/icict/50788
DOI
10.1101/2020.12.01.407361
ISSN
2470-1343