Identification of Compounds With Antiviral Activity Against SARS-CoV-2 in the MMV Pathogen Box Using a Phenotypic High-Throughput Screening Assay
Until December 2021, the COVID-19 pandemic has caused more than 5.5 million deaths. Vaccines are being deployed worldwide to mitigate severe disease and death, but continued transmission and the emergence of SARS-CoV-2 variants indicate that specific treatments against COVID-19 are still necessary....
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| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Virology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fviro.2022.854363/full |
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| author | Laís D. Coimbra Laís D. Coimbra Alexandre Borin Alexandre Borin Marina Fontoura Marina Fontoura Humberto D. Gravina Alice Nagai Jacqueline Farinha Shimizu Karina Bispo-dos-Santos Fabiana Granja Fabiana Granja Paulo S. L. Oliveira Kleber G. Franchini Kirandeep Samby Marjorie Bruder José Luiz Proença-Módena Daniela B. B. Trivella Juliana H. C. Smetana Juliana H. C. Smetana Artur T. Cordeiro Rafael Elias Marques |
| author_facet | Laís D. Coimbra Laís D. Coimbra Alexandre Borin Alexandre Borin Marina Fontoura Marina Fontoura Humberto D. Gravina Alice Nagai Jacqueline Farinha Shimizu Karina Bispo-dos-Santos Fabiana Granja Fabiana Granja Paulo S. L. Oliveira Kleber G. Franchini Kirandeep Samby Marjorie Bruder José Luiz Proença-Módena Daniela B. B. Trivella Juliana H. C. Smetana Juliana H. C. Smetana Artur T. Cordeiro Rafael Elias Marques |
| author_sort | Laís D. Coimbra |
| collection | DOAJ |
| description | Until December 2021, the COVID-19 pandemic has caused more than 5.5 million deaths. Vaccines are being deployed worldwide to mitigate severe disease and death, but continued transmission and the emergence of SARS-CoV-2 variants indicate that specific treatments against COVID-19 are still necessary. We screened 400 compounds from the Medicines for Malaria Venture (MMV) Pathogen Box seeking for molecules with antiviral activity against SARS-CoV-2 by using a high-throughput screening (HTS) infection assay in Vero CCL81 cells. On resupply of 15 selected hit compounds, we confirmed that 7 of them presented a dose-dependent cytoprotective activity against SARS-CoV-2-induced cytopathic effect (CPE) in the micromolar range. They were validated in low-throughput infection assays using four different cell lines, including the human lung Calu-3 cell line. MMV000063, MMV024937, MMV688279, and MMV688991 reduced viral load in cell culture, assessed by RT-qPCR and viral plaque assay, while MMV688279 and MMV688991 (also known as nitazoxanide) were the most promising, reducing SARS-CoV-2 load by at least 100-fold at 20 µM in almost all cell types tested. Our results indicate that active anti-SARS-CoV-2 molecules exist within the repertoire of antiviral, antiparasitic and antimicrobial compounds available to date. Although the mode of action by which MMV688279 and MMV688991 reduce SARS-CoV-2 replication is yet unknown, the fact that they were active in different cell types holds promise not only for the discovery of new therapeutic targets, but also for the development of novel antiviral medicines against COVID-19. |
| first_indexed | 2024-12-10T04:10:56Z |
| format | Article |
| id | doaj.art-a5ef3494e053423bab15254c1229c102 |
| institution | Directory Open Access Journal |
| issn | 2673-818X |
| language | English |
| last_indexed | 2024-12-10T04:10:56Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Virology |
| spelling | doaj.art-a5ef3494e053423bab15254c1229c1022022-12-22T02:02:44ZengFrontiers Media S.A.Frontiers in Virology2673-818X2022-04-01210.3389/fviro.2022.854363854363Identification of Compounds With Antiviral Activity Against SARS-CoV-2 in the MMV Pathogen Box Using a Phenotypic High-Throughput Screening AssayLaís D. Coimbra0Laís D. Coimbra1Alexandre Borin2Alexandre Borin3Marina Fontoura4Marina Fontoura5Humberto D. Gravina6Alice Nagai7Jacqueline Farinha Shimizu8Karina Bispo-dos-Santos9Fabiana Granja10Fabiana Granja11Paulo S. L. Oliveira12Kleber G. Franchini13Kirandeep Samby14Marjorie Bruder15José Luiz Proença-Módena16Daniela B. B. Trivella17Juliana H. C. Smetana18Juliana H. C. Smetana19Artur T. Cordeiro20Rafael Elias Marques21Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilDepartment of Genetics, Microbiology and Immunology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilDepartment of Genetics, Microbiology and Immunology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilDepartment of Cellular and Structural Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilLaboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, BrazilLaboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, BrazilBiodiversity Research Center, Federal University of Roraima (UFRR), Roraima, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilMedicines for Malaria Venture (MMV), Geneva, SwitzerlandBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilLaboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilIlum School of Science, Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, BrazilUntil December 2021, the COVID-19 pandemic has caused more than 5.5 million deaths. Vaccines are being deployed worldwide to mitigate severe disease and death, but continued transmission and the emergence of SARS-CoV-2 variants indicate that specific treatments against COVID-19 are still necessary. We screened 400 compounds from the Medicines for Malaria Venture (MMV) Pathogen Box seeking for molecules with antiviral activity against SARS-CoV-2 by using a high-throughput screening (HTS) infection assay in Vero CCL81 cells. On resupply of 15 selected hit compounds, we confirmed that 7 of them presented a dose-dependent cytoprotective activity against SARS-CoV-2-induced cytopathic effect (CPE) in the micromolar range. They were validated in low-throughput infection assays using four different cell lines, including the human lung Calu-3 cell line. MMV000063, MMV024937, MMV688279, and MMV688991 reduced viral load in cell culture, assessed by RT-qPCR and viral plaque assay, while MMV688279 and MMV688991 (also known as nitazoxanide) were the most promising, reducing SARS-CoV-2 load by at least 100-fold at 20 µM in almost all cell types tested. Our results indicate that active anti-SARS-CoV-2 molecules exist within the repertoire of antiviral, antiparasitic and antimicrobial compounds available to date. Although the mode of action by which MMV688279 and MMV688991 reduce SARS-CoV-2 replication is yet unknown, the fact that they were active in different cell types holds promise not only for the discovery of new therapeutic targets, but also for the development of novel antiviral medicines against COVID-19.https://www.frontiersin.org/articles/10.3389/fviro.2022.854363/fullSARS-CoV-2biosafety level 3MMV pathogen boxantiviralsdrug repositioninghigh-throughput screening |
| spellingShingle | Laís D. Coimbra Laís D. Coimbra Alexandre Borin Alexandre Borin Marina Fontoura Marina Fontoura Humberto D. Gravina Alice Nagai Jacqueline Farinha Shimizu Karina Bispo-dos-Santos Fabiana Granja Fabiana Granja Paulo S. L. Oliveira Kleber G. Franchini Kirandeep Samby Marjorie Bruder José Luiz Proença-Módena Daniela B. B. Trivella Juliana H. C. Smetana Juliana H. C. Smetana Artur T. Cordeiro Rafael Elias Marques Identification of Compounds With Antiviral Activity Against SARS-CoV-2 in the MMV Pathogen Box Using a Phenotypic High-Throughput Screening Assay Frontiers in Virology SARS-CoV-2 biosafety level 3 MMV pathogen box antivirals drug repositioning high-throughput screening |
| title | Identification of Compounds With Antiviral Activity Against SARS-CoV-2 in the MMV Pathogen Box Using a Phenotypic High-Throughput Screening Assay |
| title_full | Identification of Compounds With Antiviral Activity Against SARS-CoV-2 in the MMV Pathogen Box Using a Phenotypic High-Throughput Screening Assay |
| title_fullStr | Identification of Compounds With Antiviral Activity Against SARS-CoV-2 in the MMV Pathogen Box Using a Phenotypic High-Throughput Screening Assay |
| title_full_unstemmed | Identification of Compounds With Antiviral Activity Against SARS-CoV-2 in the MMV Pathogen Box Using a Phenotypic High-Throughput Screening Assay |
| title_short | Identification of Compounds With Antiviral Activity Against SARS-CoV-2 in the MMV Pathogen Box Using a Phenotypic High-Throughput Screening Assay |
| title_sort | identification of compounds with antiviral activity against sars cov 2 in the mmv pathogen box using a phenotypic high throughput screening assay |
| topic | SARS-CoV-2 biosafety level 3 MMV pathogen box antivirals drug repositioning high-throughput screening |
| url | https://www.frontiersin.org/articles/10.3389/fviro.2022.854363/full |
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