| Author | Puhl, Ana C. | |
| Author | Fritch, Ethan James | |
| Author | Lane, Thomas R. | |
| Author | Tse, Longping Victor | |
| Author | Yount, Boyd L. | |
| Author | Sacramento, Carolina de Queiroz | |
| Author | Rodrigues, Natalia Fintelman | |
| Author | Tavella, Tatyana Almeida | |
| Author | Costa, Fabio Trindade Maranhão | |
| Author | Weston, Stuart | |
| Author | Logue, James | |
| Author | Frieman, Matthew | |
| Author | Premkumar, Lakshmanane | |
| Author | Pearce, Kenneth H. | |
| Author | Hurst, Brett L. | |
| Author | Andrade, Carolina Horta | |
| Author | Levi, James A. | |
| Author | Johnson, Nicole J. | |
| Author | Kisthardt, Samantha C. | |
| Author | Scholle, Frank | |
| Author | Souza, Thiago Moreno Lopes e | |
| Author | Moorman, Nathaniel John | |
| Author | Baric, Ralph S. | |
| Author | Madrid, Peter B. | |
| Author | Ekins, Sean | |
| Access date | 2022-01-16T17:58:28Z | |
| Available date | 2022-01-16T17:58:28Z | |
| Document date | 2021 | |
| 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, n. 11, p. 7454-7468, 23 Mar. 2021. | |
| ISSN | 2470-1343 | |
| URI | https://www.arca.fiocruz.br/handle/icict/50764 | |
| Description | Produção científica do Laboratório de Imunofarmacologia. | pt_BR |
| Language | eng | en_US |
| Publisher | American Chemical Society | |
| Previous version | https://www.arca.fiocruz.br/handle/icict/50788 | |
| Rights | open access | |
| Subject in Portuguese | Atividade In Vitro contra SARS-CoV‑2 | pt_BR |
| Subject in Portuguese | Reaproveitando | pt_BR |
| Subject in Portuguese | Inibidores do vírus Ebola e Marburg Tilorone | pt_BR |
| Subject in Portuguese | Quinacrina e Pironaridina | pt_BR |
| Subject in Portuguese | Mecanismos Potenciais | pt_BR |
| Title | Repurposing the Ebola and Marburg virus inhibitors tilorone, quinacrine, and pyronaridine: in vitro activity against SARS-CoV‑2 and potential mechanisms | en_US |
| Type | Article | |
| DOI | 10.1101/2020.12.01.407361 | |
| 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. | en_US |
| Affilliation | Collaborations Pharmaceuticals, Inc. Raleigh, NC, USA. | |
| Affilliation | University of North Carolina. School of Medicine. Department of Microbiology and Immunology. Chapel Hill, NC, USA. | |
| Affilliation | Collaborations Pharmaceuticals, Inc. Raleigh, NC, USA. | |
| Affilliation | University of North Carolina. School of Medicine. Department of Epidemiology. Chapel Hill, NC, USA. | |
| Affilliation | University of North Carolina. School of Medicine. Department of Epidemiology. Chapel Hill, NC, USA. | |
| Affilliation | 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. | |
| Affilliation | 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. | |
| Affilliation | Universidade Estadual de Campinas. Instituto de Biologia. Departamento de Genética e Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais. Campinas, SP, Brasil. | |
| Affilliation | Universidade Estadual de Campinas. Instituto de Biologia. Departamento de Genética e Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais. Campinas, SP, Brasil. | |
| Affilliation | University of Maryland. School of Medicine. Department of Microbiology and Immunology. Baltimore, MD, USA. | |
| Affilliation | University of Maryland. School of Medicine. Department of Microbiology and Immunology. Baltimore, MD, USA. | |
| Affilliation | University of Maryland. School of Medicine. Department of Microbiology and Immunology. Baltimore, MD, USA. | |
| Affilliation | University of North Carolina. School of Medicine. Department of Microbiology and Immunology. Chapel Hill, NC, USA. | |
| Affilliation | University of North Carolina. Eshelman School of Pharmacy. Chemical Biology and Medicinal Chemistry. Center for Integrative Chemical Biology and Drug Discovery. Chapel Hill, NC, USA / University of North Carolina. Lineberger Comprehensive Cancer Center. Chapel Hill, NC, USA. | |
| Affilliation | Utah State University. Institute for Antiviral Research. Logan, UT, USA / Utah State University. Department of Animal, Dairy and Veterinary Sciences. Logan, UT, USA. | |
| Affilliation | Universidade Estadual de Campinas. Instituto de Biologia. Departamento de Genética e Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais. Campinas, SP, Brasil / Universidade Federal de Goiás. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil. | |
| Affilliation | North Carolina State University. Department of Biological Sciences. Raleigh, NC, USA. | |
| Affilliation | North Carolina State University. Department of Biological Sciences. Raleigh, NC, USA. | |
| Affilliation | North Carolina State University. Department of Biological Sciences. Raleigh, NC, USA. | |
| Affilliation | North Carolina State University. Department of Biological Sciences. Raleigh, NC, USA. | |
| Affilliation | 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. | |
| Affilliation | University of North Carolina. School of Medicine. Department of Microbiology and Immunology. Chapel Hill, NC, USA / University of North Carolina. Eshelman School of Pharmacy. Chemical Biology and Medicinal Chemistry. Center for Integrative Chemical Biology and Drug Discovery. Chapel Hill, NC, USA / University of North Carolina. Rapidly Emerging Antiviral Drug Discovery Initiative. Chapel Hill, NC, USA. | |
| Affilliation | University of North Carolina. School of Medicine. Department of Microbiology and Immunology. Chapel Hill, NC, USA / University of North Carolina. School of Medicine. Department of Epidemiology. Chapel Hill, NC, USA / University of North Carolina. Rapidly Emerging Antiviral Drug Discovery Initiative. Chapel Hill, NC, USA. | |
| Affilliation | Stanford Research Institute International. Menlo Park, CA, USA. | |
| Affilliation | Collaborations Pharmaceuticals, Inc. Raleigh, NC, USA. | |
| Subject | Vitro Activity against SARS-CoV‑2 | en_US |
| Subject | Repurposing | en_US |
| Subject | Ebola and Marburg Virus | en_US |
| Subject | Inhibitors Tilorone, Quinacrine, and Pyronaridine | en_US |
| Subject | Potential Mechanisms | en_US |
| e-ISSN | 2470-1343 | |
