The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.3390/v14071351 http://hdl.handle.net/11449/240361 |
Resumo: | Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disabling disease that can cause long-term severe arthritis. Since the last large CHIKV outbreak in 2015, the reemergence of the virus represents a serious public health concern. The morbidity associated with viral infection emphasizes the need for the development of specific anti-CHIKV drugs. Herein, we describe the development and characterization of a CHIKV reporter replicon cell line and its use in replicon-based screenings. We tested 960 compounds from MMV/DNDi Open Box libraries and identified four candidates with interesting antiviral activities, which were confirmed in viral infection assays employing CHIKV-nanoluc and BHK-21 cells. The most noteworthy compound identified was itraconazole (ITZ), an orally available, safe, and cheap antifungal, that showed high selectivity indexes of >312 and >294 in both replicon-based and viral infection assays, respectively. The antiviral activity of this molecule has been described against positive-sense single stranded RNA viruses (+ssRNA) and was related to cholesterol metabolism that could affect the formation of the replication organelles. Although its precise mechanism of action against CHIKV still needs to be elucidated, our results demonstrate that ITZ is a potent inhibitor of the viral replication that could be repurposed as a broad-spectrum antiviral. |
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The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus ReplicationantiviralChikungunya virusdrug developmentItraconazolereplicon-based assaysChikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disabling disease that can cause long-term severe arthritis. Since the last large CHIKV outbreak in 2015, the reemergence of the virus represents a serious public health concern. The morbidity associated with viral infection emphasizes the need for the development of specific anti-CHIKV drugs. Herein, we describe the development and characterization of a CHIKV reporter replicon cell line and its use in replicon-based screenings. We tested 960 compounds from MMV/DNDi Open Box libraries and identified four candidates with interesting antiviral activities, which were confirmed in viral infection assays employing CHIKV-nanoluc and BHK-21 cells. The most noteworthy compound identified was itraconazole (ITZ), an orally available, safe, and cheap antifungal, that showed high selectivity indexes of >312 and >294 in both replicon-based and viral infection assays, respectively. The antiviral activity of this molecule has been described against positive-sense single stranded RNA viruses (+ssRNA) and was related to cholesterol metabolism that could affect the formation of the replication organelles. Although its precise mechanism of action against CHIKV still needs to be elucidated, our results demonstrate that ITZ is a potent inhibitor of the viral replication that could be repurposed as a broad-spectrum antiviral.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)São Carlos Institute of Physics University of São PauloVirology Sector Department of Preventive Veterinary Medicine Federal University of Santa MariaVirology Sector Laboratory of Immunopathology Keizo Asami Federal University of PernambucoInstitute of Biomedical Sciences Federal University of UberlândiaInstitute of Biosciences Humanities and Exact Sciences (Ibilce) São Paulo State University (UNESP), Campus São José do Rio PretoMedicines for Malaria Venture, P.O. Box 1826Aggeu Magalhães Institute IAM-FIOCRUZInstitute of Biosciences Humanities and Exact Sciences (Ibilce) São Paulo State University (UNESP), Campus São José do Rio PretoCAPES: #88887.479203/2020-00FAPESP: 2013/07600-3CNPq: 440773/2019-8Universidade de São Paulo (USP)Federal University of Santa MariaUniversidade Federal de Pernambuco (UFPE)Universidade Federal de Uberlândia (UFU)Universidade Estadual Paulista (UNESP)Medicines for Malaria VentureIAM-FIOCRUZPolicastro, Lucca R.Dolci, IsabelaGodoy, Andre S.Silva Júnior, José V. J.Ruiz, Uriel E. A.Santos, Igor A.Jardim, Ana C. G. [UNESP]Samby, KirandeepBurrows, Jeremy N.Wells, Timothy N. C.Gil, Laura H. V. G.Oliva, GlauciusFernandes, Rafaela S.2023-03-01T20:13:40Z2023-03-01T20:13:40Z2022-07-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.3390/v14071351Viruses, v. 14, n. 7, 2022.1999-4915http://hdl.handle.net/11449/24036110.3390/v140713512-s2.0-85133014593Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengVirusesinfo:eu-repo/semantics/openAccess2023-03-01T20:13:40Zoai:repositorio.unesp.br:11449/240361Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462023-03-01T20:13:40Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication |
title |
The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication |
spellingShingle |
The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication Policastro, Lucca R. antiviral Chikungunya virus drug development Itraconazole replicon-based assays |
title_short |
The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication |
title_full |
The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication |
title_fullStr |
The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication |
title_full_unstemmed |
The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication |
title_sort |
The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication |
author |
Policastro, Lucca R. |
author_facet |
Policastro, Lucca R. Dolci, Isabela Godoy, Andre S. Silva Júnior, José V. J. Ruiz, Uriel E. A. Santos, Igor A. Jardim, Ana C. G. [UNESP] Samby, Kirandeep Burrows, Jeremy N. Wells, Timothy N. C. Gil, Laura H. V. G. Oliva, Glaucius Fernandes, Rafaela S. |
author_role |
author |
author2 |
Dolci, Isabela Godoy, Andre S. Silva Júnior, José V. J. Ruiz, Uriel E. A. Santos, Igor A. Jardim, Ana C. G. [UNESP] Samby, Kirandeep Burrows, Jeremy N. Wells, Timothy N. C. Gil, Laura H. V. G. Oliva, Glaucius Fernandes, Rafaela S. |
author2_role |
author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade de São Paulo (USP) Federal University of Santa Maria Universidade Federal de Pernambuco (UFPE) Universidade Federal de Uberlândia (UFU) Universidade Estadual Paulista (UNESP) Medicines for Malaria Venture IAM-FIOCRUZ |
dc.contributor.author.fl_str_mv |
Policastro, Lucca R. Dolci, Isabela Godoy, Andre S. Silva Júnior, José V. J. Ruiz, Uriel E. A. Santos, Igor A. Jardim, Ana C. G. [UNESP] Samby, Kirandeep Burrows, Jeremy N. Wells, Timothy N. C. Gil, Laura H. V. G. Oliva, Glaucius Fernandes, Rafaela S. |
dc.subject.por.fl_str_mv |
antiviral Chikungunya virus drug development Itraconazole replicon-based assays |
topic |
antiviral Chikungunya virus drug development Itraconazole replicon-based assays |
description |
Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disabling disease that can cause long-term severe arthritis. Since the last large CHIKV outbreak in 2015, the reemergence of the virus represents a serious public health concern. The morbidity associated with viral infection emphasizes the need for the development of specific anti-CHIKV drugs. Herein, we describe the development and characterization of a CHIKV reporter replicon cell line and its use in replicon-based screenings. We tested 960 compounds from MMV/DNDi Open Box libraries and identified four candidates with interesting antiviral activities, which were confirmed in viral infection assays employing CHIKV-nanoluc and BHK-21 cells. The most noteworthy compound identified was itraconazole (ITZ), an orally available, safe, and cheap antifungal, that showed high selectivity indexes of >312 and >294 in both replicon-based and viral infection assays, respectively. The antiviral activity of this molecule has been described against positive-sense single stranded RNA viruses (+ssRNA) and was related to cholesterol metabolism that could affect the formation of the replication organelles. Although its precise mechanism of action against CHIKV still needs to be elucidated, our results demonstrate that ITZ is a potent inhibitor of the viral replication that could be repurposed as a broad-spectrum antiviral. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-07-01 2023-03-01T20:13:40Z 2023-03-01T20:13:40Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.3390/v14071351 Viruses, v. 14, n. 7, 2022. 1999-4915 http://hdl.handle.net/11449/240361 10.3390/v14071351 2-s2.0-85133014593 |
url |
http://dx.doi.org/10.3390/v14071351 http://hdl.handle.net/11449/240361 |
identifier_str_mv |
Viruses, v. 14, n. 7, 2022. 1999-4915 10.3390/v14071351 2-s2.0-85133014593 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Viruses |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
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1803650371229319168 |