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Identification and characterization of the anti-SARS-CoV-2 activity of cationic amphiphilic steroidal compounds.
Borin, Alexandre; Coimbra, Laís D; Bispo-Dos-Santos, Karina; Naciuk, Fabrício F; Fontoura, Marina; Simeoni, Camila L; Gomes, Giovanni V; Amorim, Mariene R; Gravina, Humberto D; Shimizu, Jacqueline Farinha; Passos, Amanda S C; de Oliveira, Isadora M; de Carvalho, Ana Carolina; Cardoso, Alisson Campos; Parise, Pierina L; Toledo-Teixeira, Daniel A; Sotorilli, Giuliana E; Persinoti, Gabriela F; Claro, Ingra Morales; Sabino, Ester C; Alborghetti, Marcos R; Rocco, Silvana A; Franchini, Kleber G; de Souza, William M; Oliveira, Paulo S L; Cunha, Thiago M; Granja, Fabiana; Proença-Módena, José Luiz; Trivella, Daniela B B; Bruder, Marjorie; Cordeiro, Artur T; Marques, Rafael Elias.
  • Borin A; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Coimbra LD; Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Bispo-Dos-Santos K; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Naciuk FF; Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Fontoura M; Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Simeoni CL; Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Gomes GV; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Amorim MR; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Gravina HD; Department of Cellular and Structural Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Shimizu JF; Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Passos ASC; Center for Research in Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
  • de Oliveira IM; Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • de Carvalho AC; Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Cardoso AC; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Parise PL; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Toledo-Teixeira DA; Center for Research in Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
  • Sotorilli GE; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Persinoti GF; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Claro IM; Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Sabino EC; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Alborghetti MR; Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Rocco SA; Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Franchini KG; Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • de Souza WM; Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Oliveira PSL; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Cunha TM; Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Granja F; Brazilian Biorenewables National Laboratory (LNBR), Brazilian Center for Research in Energy and Materials (CNPEM), São Paulo, Brazil.
  • Proença-Módena JL; Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
  • Trivella DBB; Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
  • Bruder M; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Cordeiro AT; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
  • Marques RE; Brazilian Biosciences National Laboratory - LNBio, Brazilian Center for Research in Energy and Materials - CNPEM, Campinas, Brazil.
Virulence ; 13(1): 1031-1048, 2022 12.
Article in English | MEDLINE | ID: covidwho-1900978
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Virulence Year: 2022 Document Type: Article Affiliation country: 21505594.2022.2085793

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Virulence Year: 2022 Document Type: Article Affiliation country: 21505594.2022.2085793