Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2016 |
| Outros Autores: | , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/17829 |
Resumo: | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil. |
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Andrade Neto, Valter VianaCunha Junior, Edézio FerreiraCavalheiro, Marilene Marcuzzo do CantoAtella, Georgia CorreaFernandes, Talita de AlmeidaCosta, Paulo Roberto RibeiroSantos, Eduardo Caio Torres2017-02-16T11:11:30Z2017-02-16T11:11:30Z2016ANDRADE NETO, Valter Viana; et al. Antileishmanial activity of ezetimibe: inhibition of sterol biosynthesis, in vitro synergy with azoles and efficacious in experimental cutaneous leishmaniasis. Antimicrob. Agents Chemother., 25p, Sept. 2016.0066-4804https://www.arca.fiocruz.br/handle/icict/1782910.1128/AAC.01545-161098-6596engAmerican Society for MicrobiologyAzóisEzetimibaLeishmania amazonensisReposicionamento de MedicamentosBiossíntese de esteróisSterol biosynthesisLeishmania amazonensisazolesezetimibedrug repositioningAntileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasisinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Pesquisas de Produtos Naturais. Laboratório de Química Bioorgânica. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Pesquisas de Produtos Naturais. Laboratório de Química Bioorgânica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Leishmaniasis affects mainly low-income populations in tropical regions. Radical innovation in drug discovery is time-consuming and expensive, imposing severe restrictions on the ability to launch new chemical entities for the treatment of neglected diseases. Drug repositioning is an attractive strategy for addressing a specific demand more easily. In this project, we have evaluated the antileishmanial activities of 30 drugs currently in clinical use for various morbidities. Ezetimibe, clinically used to reduce intestinal cholesterol absorption in dyslipidemic patients, killed Leishmania amazonensis promastigotes with a 50% inhibitory concentration (IC50) of 30 μM. Morphological analysis revealed that ezetimibe caused the parasites to become rounded, with multiple nuclei and flagella. Analysis by gas chromatography (GC)-mass spectrometry (MS) showed that promastigotes treated with ezetimibe had smaller amounts of C-14-demethylated sterols, and accumulated more cholesterol and lanosterol, than untreated promastigotes. We then evaluated the combination of ezetimibe with well-known antileishmanial azoles. The fractional inhibitory concentration index (FICI) indicated synergy when ezetimibe was combined with ketoconazole or miconazole. The activity of ezetimibe against intracellular amastigotes was confirmed, with an IC50 of 20 μM, and ezetimibe reduced the IC90s of ketoconazole and miconazole from 11.3 and 11.5 μM to 4.14 and 8.25 μM, respectively. Subsequently, we confirmed the activity of ezetimibe in vivo, showing that it decreased lesion development and parasite loads in murine cutaneous leishmaniasis. We concluded that ezetimibe has promising antileishmanial activity and should be considered in combination with azoles in further preclinical and clinical studies.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/17829/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALve_marilene_cavalheiro_etal_IOC_2016.pdfve_marilene_cavalheiro_etal_IOC_2016.pdfVersão do Editorapplication/pdf2120041https://www.arca.fiocruz.br/bitstream/icict/17829/3/ve_marilene_cavalheiro_etal_IOC_2016.pdf06f9a5ab6471257ab1a9e412bd950628MD53marilene_cavalheiro_etal_IOC_2016.pdfmarilene_cavalheiro_etal_IOC_2016.pdfAccepted 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| dc.title.pt_BR.fl_str_mv |
Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis |
| title |
Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis |
| spellingShingle |
Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis Andrade Neto, Valter Viana Azóis Ezetimiba Leishmania amazonensis Reposicionamento de Medicamentos Biossíntese de esteróis Sterol biosynthesis Leishmania amazonensis azoles ezetimibe drug repositioning |
| title_short |
Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis |
| title_full |
Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis |
| title_fullStr |
Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis |
| title_full_unstemmed |
Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis |
| title_sort |
Antileishmanial Activity of Ezetimibe: Inhibition of Sterol Biosynthesis, In Vitro Synergy with Azoles, and Efficacy in Experimental Cutaneous Leishmaniasis |
| author |
Andrade Neto, Valter Viana |
| author_facet |
Andrade Neto, Valter Viana Cunha Junior, Edézio Ferreira Cavalheiro, Marilene Marcuzzo do Canto Atella, Georgia Correa Fernandes, Talita de Almeida Costa, Paulo Roberto Ribeiro Santos, Eduardo Caio Torres |
| author_role |
author |
| author2 |
Cunha Junior, Edézio Ferreira Cavalheiro, Marilene Marcuzzo do Canto Atella, Georgia Correa Fernandes, Talita de Almeida Costa, Paulo Roberto Ribeiro Santos, Eduardo Caio Torres |
| author2_role |
author author author author author author |
| dc.contributor.author.fl_str_mv |
Andrade Neto, Valter Viana Cunha Junior, Edézio Ferreira Cavalheiro, Marilene Marcuzzo do Canto Atella, Georgia Correa Fernandes, Talita de Almeida Costa, Paulo Roberto Ribeiro Santos, Eduardo Caio Torres |
| dc.subject.other.pt_BR.fl_str_mv |
Azóis Ezetimiba Leishmania amazonensis Reposicionamento de Medicamentos Biossíntese de esteróis |
| topic |
Azóis Ezetimiba Leishmania amazonensis Reposicionamento de Medicamentos Biossíntese de esteróis Sterol biosynthesis Leishmania amazonensis azoles ezetimibe drug repositioning |
| dc.subject.en.pt_BR.fl_str_mv |
Sterol biosynthesis Leishmania amazonensis azoles ezetimibe drug repositioning |
| description |
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil. |
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2016 |
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2016 |
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2017-02-16T11:11:30Z |
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2017-02-16T11:11:30Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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ANDRADE NETO, Valter Viana; et al. Antileishmanial activity of ezetimibe: inhibition of sterol biosynthesis, in vitro synergy with azoles and efficacious in experimental cutaneous leishmaniasis. Antimicrob. Agents Chemother., 25p, Sept. 2016. |
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https://www.arca.fiocruz.br/handle/icict/17829 |
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0066-4804 |
| dc.identifier.doi.none.fl_str_mv |
10.1128/AAC.01545-16 |
| dc.identifier.eissn.none.fl_str_mv |
1098-6596 |
| identifier_str_mv |
ANDRADE NETO, Valter Viana; et al. Antileishmanial activity of ezetimibe: inhibition of sterol biosynthesis, in vitro synergy with azoles and efficacious in experimental cutaneous leishmaniasis. Antimicrob. Agents Chemother., 25p, Sept. 2016. 0066-4804 10.1128/AAC.01545-16 1098-6596 |
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American Society for Microbiology |
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American Society for Microbiology |
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