Phenotypical Screening of an MMV Open Box Library and Identification of Compounds with Antiviral Activity against St. Louis Encephalitis Virus
St. Louis encephalitis virus (SLEV) is a neglected mosquito-borne Flavivirus that may cause severe neurological disease in humans and other animals. There are no specific treatments against SLEV infection or disease approved for human use, and drug repurposing may represent an opportunity to acceler...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/12/2416 |
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| author | Giuliana Eboli Sotorilli Humberto Doriguetto Gravina Ana Carolina de Carvalho Jacqueline Farinha Shimizu Marina Alves Fontoura Talita Diniz Melo-Hanchuk Artur Torres Cordeiro Rafael Elias Marques |
| author_facet | Giuliana Eboli Sotorilli Humberto Doriguetto Gravina Ana Carolina de Carvalho Jacqueline Farinha Shimizu Marina Alves Fontoura Talita Diniz Melo-Hanchuk Artur Torres Cordeiro Rafael Elias Marques |
| author_sort | Giuliana Eboli Sotorilli |
| collection | DOAJ |
| description | St. Louis encephalitis virus (SLEV) is a neglected mosquito-borne Flavivirus that may cause severe neurological disease in humans and other animals. There are no specific treatments against SLEV infection or disease approved for human use, and drug repurposing may represent an opportunity to accelerate the development of treatments against SLEV. Here we present a scalable, medium-throughput phenotypic cell culture-based screening assay on Vero CCL81 cells to identify bioactive compounds that could be repurposed against SLEV infection. We screened eighty compounds from the Medicines for Malaria Venture (MMV) COVID Box library to identify nine (11%) compounds that protected cell cultures from SLEV-induced cytopathic effects, with low- to mid-micromolar potencies. We validated six hit compounds using viral plaque-forming assays to find that the compounds ABT-239, Amiodarone, Fluphenazine, Posaconazole, Triparanol, and Vidofludimus presented varied levels of antiviral activity and selectivity depending on the mammalian cell type used for testing. Importantly, we identified and validated the antiviral activity of the anti-flavivirus nucleoside analog 7DMA against SLEV. Triparanol and Fluphenazine reduced infectious viral loads in both Vero CCL81 and HBEC-5i cell cultures and, similar to the other validated compounds, are likely to exert antiviral activity through a molecular target in the host. |
| first_indexed | 2024-03-08T20:17:31Z |
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| id | doaj.art-c234a3b208bc4d74b360b91207ddd778 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-08T20:17:31Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-c234a3b208bc4d74b360b91207ddd7782023-12-22T14:49:23ZengMDPI AGViruses1999-49152023-12-011512241610.3390/v15122416Phenotypical Screening of an MMV Open Box Library and Identification of Compounds with Antiviral Activity against St. Louis Encephalitis VirusGiuliana Eboli Sotorilli0Humberto Doriguetto Gravina1Ana Carolina de Carvalho2Jacqueline Farinha Shimizu3Marina Alves Fontoura4Talita Diniz Melo-Hanchuk5Artur Torres Cordeiro6Rafael Elias Marques7Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-100, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-100, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-100, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-100, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-100, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-100, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-100, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-100, BrazilSt. Louis encephalitis virus (SLEV) is a neglected mosquito-borne Flavivirus that may cause severe neurological disease in humans and other animals. There are no specific treatments against SLEV infection or disease approved for human use, and drug repurposing may represent an opportunity to accelerate the development of treatments against SLEV. Here we present a scalable, medium-throughput phenotypic cell culture-based screening assay on Vero CCL81 cells to identify bioactive compounds that could be repurposed against SLEV infection. We screened eighty compounds from the Medicines for Malaria Venture (MMV) COVID Box library to identify nine (11%) compounds that protected cell cultures from SLEV-induced cytopathic effects, with low- to mid-micromolar potencies. We validated six hit compounds using viral plaque-forming assays to find that the compounds ABT-239, Amiodarone, Fluphenazine, Posaconazole, Triparanol, and Vidofludimus presented varied levels of antiviral activity and selectivity depending on the mammalian cell type used for testing. Importantly, we identified and validated the antiviral activity of the anti-flavivirus nucleoside analog 7DMA against SLEV. Triparanol and Fluphenazine reduced infectious viral loads in both Vero CCL81 and HBEC-5i cell cultures and, similar to the other validated compounds, are likely to exert antiviral activity through a molecular target in the host.https://www.mdpi.com/1999-4915/15/12/2416St. Louis encephalitis viruscell culture-based screeningdrug repurposingFlaviviruscationic amphiphilic compounds (CAD) |
| spellingShingle | Giuliana Eboli Sotorilli Humberto Doriguetto Gravina Ana Carolina de Carvalho Jacqueline Farinha Shimizu Marina Alves Fontoura Talita Diniz Melo-Hanchuk Artur Torres Cordeiro Rafael Elias Marques Phenotypical Screening of an MMV Open Box Library and Identification of Compounds with Antiviral Activity against St. Louis Encephalitis Virus Viruses St. Louis encephalitis virus cell culture-based screening drug repurposing Flavivirus cationic amphiphilic compounds (CAD) |
| title | Phenotypical Screening of an MMV Open Box Library and Identification of Compounds with Antiviral Activity against St. Louis Encephalitis Virus |
| title_full | Phenotypical Screening of an MMV Open Box Library and Identification of Compounds with Antiviral Activity against St. Louis Encephalitis Virus |
| title_fullStr | Phenotypical Screening of an MMV Open Box Library and Identification of Compounds with Antiviral Activity against St. Louis Encephalitis Virus |
| title_full_unstemmed | Phenotypical Screening of an MMV Open Box Library and Identification of Compounds with Antiviral Activity against St. Louis Encephalitis Virus |
| title_short | Phenotypical Screening of an MMV Open Box Library and Identification of Compounds with Antiviral Activity against St. Louis Encephalitis Virus |
| title_sort | phenotypical screening of an mmv open box library and identification of compounds with antiviral activity against st louis encephalitis virus |
| topic | St. Louis encephalitis virus cell culture-based screening drug repurposing Flavivirus cationic amphiphilic compounds (CAD) |
| url | https://www.mdpi.com/1999-4915/15/12/2416 |
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