Identification and characterization of the anti-SARS-CoV-2 activity of cationic amphiphilic steroidal compounds
The ongoing COVID-19 pandemic caused a significant loss of human lives and a worldwide decline in quality of life. Treatment of COVID-19 patients is challenging, and specific treatments to reduce COVID-19 aggravation and mortality are still necessary. Here, we describe the discovery of a novel class...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Virulence |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/21505594.2022.2085793 |
| _version_ | 1828723164342910976 |
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| author | Alexandre Borin Laís D. Coimbra Karina Bispo-dos-Santos Fabrício F. Naciuk Marina Fontoura Camila L. Simeoni Giovanni F. Gomes Mariene R. Amorim Humberto D. Gravina Jacqueline Farinha Shimizu Amanda S. C. Passos Isadora M. de Oliveira Ana Carolina de Carvalho Alisson Campos Cardoso Pierina L. Parise Daniel A. Toledo-Teixeira Giuliana E. Sotorilli Gabriela F. Persinoti Ingra Morales Claro Ester C. Sabino Marcos R. Alborghetti Silvana A. Rocco Kleber G. Franchini William M. de Souza Paulo S. L. Oliveira Thiago M. Cunha Fabiana Granja José Luiz Proença-Módena Daniela B.B. Trivella Marjorie Bruder Artur T. Cordeiro Rafael Elias Marques |
| author_facet | Alexandre Borin Laís D. Coimbra Karina Bispo-dos-Santos Fabrício F. Naciuk Marina Fontoura Camila L. Simeoni Giovanni F. Gomes Mariene R. Amorim Humberto D. Gravina Jacqueline Farinha Shimizu Amanda S. C. Passos Isadora M. de Oliveira Ana Carolina de Carvalho Alisson Campos Cardoso Pierina L. Parise Daniel A. Toledo-Teixeira Giuliana E. Sotorilli Gabriela F. Persinoti Ingra Morales Claro Ester C. Sabino Marcos R. Alborghetti Silvana A. Rocco Kleber G. Franchini William M. de Souza Paulo S. L. Oliveira Thiago M. Cunha Fabiana Granja José Luiz Proença-Módena Daniela B.B. Trivella Marjorie Bruder Artur T. Cordeiro Rafael Elias Marques |
| author_sort | Alexandre Borin |
| collection | DOAJ |
| description | The ongoing COVID-19 pandemic caused a significant loss of human lives and a worldwide decline in quality of life. Treatment of COVID-19 patients is challenging, and specific treatments to reduce COVID-19 aggravation and mortality are still necessary. Here, we describe the discovery of a novel class of epiandrosterone steroidal compounds with cationic amphiphilic properties that present antiviral activity against SARS-CoV-2 in the low micromolar range. Compounds were identified in screening campaigns using a cytopathic effect-based assay in Vero CCL81 cells, followed by hit compound validation and characterization. Compounds LNB167 and LNB169 were selected due to their ability to reduce the levels of infectious viral progeny and viral RNA levels in Vero CCL81, HEK293, and HuH7.5 cell lines. Mechanistic studies in Vero CCL81 cells indicated that LNB167 and LNB169 inhibited the initial phase of viral replication through mechanisms involving modulation of membrane lipids and cholesterol in host cells. Selection of viral variants resistant to steroidal compound treatment revealed single mutations on transmembrane, lipid membrane-interacting Spike and Envelope proteins. Finally, in vivo testing using the hACE2 transgenic mouse model indicated that SARS-CoV-2 infection could not be ameliorated by LNB167 treatment. We conclude that anti-SARS-CoV-2 activities of steroidal compounds LNB167 and LNB169 are likely host-targeted, consistent with the properties of cationic amphiphilic compounds that modulate host cell lipid biology. Although effective in vitro, protective effects were cell-type specific and did not translate to protection in vivo, indicating that subversion of lipid membrane physiology is an important, yet complex mechanism involved in SARS-CoV-2 replication and pathogenesis. |
| first_indexed | 2024-04-12T12:45:56Z |
| format | Article |
| id | doaj.art-72c2c6f47ab64b468b8394b05cb4b8c0 |
| institution | Directory Open Access Journal |
| issn | 2150-5594 2150-5608 |
| language | English |
| last_indexed | 2024-04-12T12:45:56Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Virulence |
| spelling | doaj.art-72c2c6f47ab64b468b8394b05cb4b8c02022-12-22T03:32:37ZengTaylor & Francis GroupVirulence2150-55942150-56082022-12-011311031104810.1080/21505594.2022.2085793Identification and characterization of the anti-SARS-CoV-2 activity of cationic amphiphilic steroidal compoundsAlexandre Borin0Laís D. Coimbra1Karina Bispo-dos-Santos2Fabrício F. Naciuk3Marina Fontoura4Camila L. Simeoni5Giovanni F. Gomes6Mariene R. Amorim7Humberto D. Gravina8Jacqueline Farinha Shimizu9Amanda S. C. Passos10Isadora M. de Oliveira11Ana Carolina de Carvalho12Alisson Campos Cardoso13Pierina L. Parise14Daniel A. Toledo-Teixeira15Giuliana E. Sotorilli16Gabriela F. Persinoti17Ingra Morales Claro18Ester C. Sabino19Marcos R. Alborghetti20Silvana A. Rocco21Kleber G. Franchini22William M. de Souza23Paulo S. L. Oliveira24Thiago M. Cunha25Fabiana Granja26José Luiz Proença-Módena27Daniela B.B. Trivella28Marjorie Bruder29Artur T. Cordeiro30Rafael Elias Marques31Brazilian 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, BrazilDepartment of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, 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, BrazilLaboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, BrazilCenter for Research in Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, BrazilDepartment of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, 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, BrazilCenter for Research in Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, 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, BrazilDepartment of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, BrazilDepartment of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, BrazilBrazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, BrazilBrazilian Biorenewables National Laboratory (LNBR), Brazilian Center for Research in Energy and Materials (CNPEM), São Paulo, BrazilInstituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, BrazilInstituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, 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, BrazilWorld Reference Center for Emerging Viruses and Arboviruses and Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USABrazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, BrazilCenter for Research in Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, BrazilLaboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, BrazilLaboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, 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, BrazilBrazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, BrazilThe ongoing COVID-19 pandemic caused a significant loss of human lives and a worldwide decline in quality of life. Treatment of COVID-19 patients is challenging, and specific treatments to reduce COVID-19 aggravation and mortality are still necessary. Here, we describe the discovery of a novel class of epiandrosterone steroidal compounds with cationic amphiphilic properties that present antiviral activity against SARS-CoV-2 in the low micromolar range. Compounds were identified in screening campaigns using a cytopathic effect-based assay in Vero CCL81 cells, followed by hit compound validation and characterization. Compounds LNB167 and LNB169 were selected due to their ability to reduce the levels of infectious viral progeny and viral RNA levels in Vero CCL81, HEK293, and HuH7.5 cell lines. Mechanistic studies in Vero CCL81 cells indicated that LNB167 and LNB169 inhibited the initial phase of viral replication through mechanisms involving modulation of membrane lipids and cholesterol in host cells. Selection of viral variants resistant to steroidal compound treatment revealed single mutations on transmembrane, lipid membrane-interacting Spike and Envelope proteins. Finally, in vivo testing using the hACE2 transgenic mouse model indicated that SARS-CoV-2 infection could not be ameliorated by LNB167 treatment. We conclude that anti-SARS-CoV-2 activities of steroidal compounds LNB167 and LNB169 are likely host-targeted, consistent with the properties of cationic amphiphilic compounds that modulate host cell lipid biology. Although effective in vitro, protective effects were cell-type specific and did not translate to protection in vivo, indicating that subversion of lipid membrane physiology is an important, yet complex mechanism involved in SARS-CoV-2 replication and pathogenesis.https://www.tandfonline.com/doi/10.1080/21505594.2022.2085793SARS-CoV-2drug discoverysteroidal compoundsantiviral activity |
| spellingShingle | Alexandre Borin Laís D. Coimbra Karina Bispo-dos-Santos Fabrício F. Naciuk Marina Fontoura Camila L. Simeoni Giovanni F. Gomes Mariene R. Amorim Humberto D. Gravina Jacqueline Farinha Shimizu Amanda S. C. Passos Isadora M. de Oliveira Ana Carolina de Carvalho Alisson Campos Cardoso Pierina L. Parise Daniel A. Toledo-Teixeira Giuliana E. Sotorilli Gabriela F. Persinoti Ingra Morales Claro Ester C. Sabino Marcos R. Alborghetti Silvana A. Rocco Kleber G. Franchini William M. de Souza Paulo S. L. Oliveira Thiago M. Cunha Fabiana Granja José Luiz Proença-Módena Daniela B.B. Trivella Marjorie Bruder Artur T. Cordeiro Rafael Elias Marques Identification and characterization of the anti-SARS-CoV-2 activity of cationic amphiphilic steroidal compounds Virulence SARS-CoV-2 drug discovery steroidal compounds antiviral activity |
| title | Identification and characterization of the anti-SARS-CoV-2 activity of cationic amphiphilic steroidal compounds |
| title_full | Identification and characterization of the anti-SARS-CoV-2 activity of cationic amphiphilic steroidal compounds |
| title_fullStr | Identification and characterization of the anti-SARS-CoV-2 activity of cationic amphiphilic steroidal compounds |
| title_full_unstemmed | Identification and characterization of the anti-SARS-CoV-2 activity of cationic amphiphilic steroidal compounds |
| title_short | Identification and characterization of the anti-SARS-CoV-2 activity of cationic amphiphilic steroidal compounds |
| title_sort | identification and characterization of the anti sars cov 2 activity of cationic amphiphilic steroidal compounds |
| topic | SARS-CoV-2 drug discovery steroidal compounds antiviral activity |
| url | https://www.tandfonline.com/doi/10.1080/21505594.2022.2085793 |
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