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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 - SHORT RUNNING TITLE: EBOLA SARS-COV-2 INHIBITORS
https://www.arca.fiocruz.br/handle/icict/50764
Author
Puhl, Ana C.
Fritch, Ethan James
Lane, Thomas R.
Tse, Longping Victor
Yount, Boyd L.
Sacramento, Carol Queiroz
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
Ekins, Sean
Fritch, Ethan James
Lane, Thomas R.
Tse, Longping Victor
Yount, Boyd L.
Sacramento, Carol Queiroz
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
Ekins, Sean
Affilliation
Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive. Lab 3510, Raleigh, NC 27606, USA.
Department of Microbiology and Immunology, University of North Carolina School of Medicine. Chapel Hill NC 27599, USA.
Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive. Lab 3510, Raleigh, NC 27606, USA.
University of North Carolina School of Medicine. Department of Epidemiology. Chapel Hill NC 27599, USA.
University of North Carolina School of Medicine. Department of Epidemiology. Chapel Hill NC 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. Rio de Janeiro, RJ, Brasil.
Universidade de Campinas. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Dr. Luiz Jacinto da Silva. Campinas, SP, Brasil.
Universidade de Campinas. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Dr. Luiz Jacinto da Silva. Campinas, SP, Brasil.
University of Maryland School of Medicine. Department of Microbiology and Immunology. Baltimore, Maryland, USA.
University of Maryland School of Medicine. Department of Microbiology and Immunology. Baltimore, Maryland, USA.
University of Maryland School of Medicine. Department of Microbiology and Immunology. Baltimore, Maryland, USA.
Department of Microbiology and Immunology, University of North Carolina School of Medicine. Chapel Hill NC 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 / iUNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
Institute for Antiviral Research, Utah State University, Logan, UT, USA / Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
Universidade de Campinas. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Dr. Luiz Jacinto da Silva. Campinas, SP, Brasil / Universidade Federal de Goiás. Faculade de Farmácia. LabMol - Laboratório de Modelagem Molecular e Design de Fármacos. Goiânia, GO, Brasil.
Department of Biological Sciences, North Carolina State University. Raleigh, NC, USA.
Department of Biological Sciences, North Carolina State University. Raleigh, NC, USA.
Department of Biological Sciences, North Carolina State University. Raleigh, NC, USA.
Department of Biological Sciences, North Carolina State University. Raleigh, NC, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill NC 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, NC, USA.
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA / Department of Epidemiology, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA / Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
SRI International, 333 Ravenswood Avenue, Menlo Park. CA 94025, USA.
Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC 27606, USA.
Department of Microbiology and Immunology, University of North Carolina School of Medicine. Chapel Hill NC 27599, USA.
Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive. Lab 3510, Raleigh, NC 27606, USA.
University of North Carolina School of Medicine. Department of Epidemiology. Chapel Hill NC 27599, USA.
University of North Carolina School of Medicine. Department of Epidemiology. Chapel Hill NC 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. Rio de Janeiro, RJ, Brasil.
Universidade de Campinas. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Dr. Luiz Jacinto da Silva. Campinas, SP, Brasil.
Universidade de Campinas. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Dr. Luiz Jacinto da Silva. Campinas, SP, Brasil.
University of Maryland School of Medicine. Department of Microbiology and Immunology. Baltimore, Maryland, USA.
University of Maryland School of Medicine. Department of Microbiology and Immunology. Baltimore, Maryland, USA.
University of Maryland School of Medicine. Department of Microbiology and Immunology. Baltimore, Maryland, USA.
Department of Microbiology and Immunology, University of North Carolina School of Medicine. Chapel Hill NC 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 / iUNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
Institute for Antiviral Research, Utah State University, Logan, UT, USA / Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
Universidade de Campinas. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Dr. Luiz Jacinto da Silva. Campinas, SP, Brasil / Universidade Federal de Goiás. Faculade de Farmácia. LabMol - Laboratório de Modelagem Molecular e Design de Fármacos. Goiânia, GO, Brasil.
Department of Biological Sciences, North Carolina State University. Raleigh, NC, USA.
Department of Biological Sciences, North Carolina State University. Raleigh, NC, USA.
Department of Biological Sciences, North Carolina State University. Raleigh, NC, USA.
Department of Biological Sciences, North Carolina State University. Raleigh, NC, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill NC 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, NC, USA.
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA / Department of Epidemiology, University of North Carolina School of Medicine, Chapel Hill NC 27599, USA / Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
SRI International, 333 Ravenswood Avenue, Menlo Park. CA 94025, USA.
Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC 27606, USA.
Abstract
SARS-CoV-2 is a newly identified virus that has resulted in over 1.3 M deaths globally and over 59 M cases globally to date. 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 virus 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 virus would seem 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 virus in vitro in HeLa cells and of mouse adapted Ebola virus in mouse 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 have also tested them in a pseudovirus assay and used microscale thermophoresis to test the binding of these molecules to the spike protein. They bind to spike RBD protein with Kd values of 339 nM and 647 nM,justifying in vivo evaluation. We also provide novel insights into their mechanism which is likely lysosomotropic. respectively. Human Cmax for pyronaridine and quinacrine is greater than the IC50 hence.
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