CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2012 |
| 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/15705 |
Resumo: | Vanderbilt University. School of Medicine. Department of Biochemistry. Nashville, TN, USA. |
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Hargrove, Tatiana Y.Kim, KwanghoSoeiro, Maria de Nazaré CorreiaSilva, Cristiane França daBatista, Denise da Gama JaenBatista, Marcos MeuserYazlovitskaya, Eugenia M.Waterman, Michael R.Sulikowski, Gary A.Lepesheva, Galina I.2016-09-06T16:23:08Z2016-09-06T16:23:08Z2012HARGROVE, Tatiana Y. et al. CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds. International Journal for Parasitology: Drugs and Drug Resistance, v.2, p.178–186, 2012.2211-3207https://www.arca.fiocruz.br/handle/icict/1570510.1016/j.ijpddr.2012.06.001engSpringer VerlagInibiçãoEstrutura de cristalEsteróis 14α-demethylaseCYP51Crystal structureInhibitionSterol 14α-demethylaseCYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffoldsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleVanderbilt University. School of Medicine. Department of Biochemistry. Nashville, TN, USA.Vanderbilt University. Vanderbilt Institute of Chemical Biology. Department of Chemistry. Nashville, TN, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Vanderbilt University. School of Medicine. Department of Medicine. Vanderbilt Ingram Cancer Center. Nashville, TN, USA.Vanderbilt University. School of Medicine. Department of Biochemistry. Nashville, TN, USA.Vanderbilt University. Vanderbilt Institute of Chemical Biology. Department of Chemistry. Nashville, TN, USA.Vanderbilt University. School of Medicine. Department of Biochemistry. Nashville, TN, USA.CYP51 (sterol 14α-demethylase) is a cytochrome P450 enzyme essential for sterol biosynthesis and the primary target for clinical and agricultural antifungal azoles. The azoles that are currently in clinical use for systemic fungal infections represent modifications of two basic scaffolds, ketoconazole and fluconazole, all of them being selected based on their antiparasitic activity in cellular experiments. By studying direct inhibition of CYP51 activity across phylogeny including human pathogens Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum, we identified three novel protozoa-specific inhibitory scaffolds, their inhibitory potency correlating well with antiprotozoan activity. VNI scaffold (carboxamide containing β-phenyl-imidazoles) is the most promising among them: killing T. cruzi amastigotes at low nanomolar concentration, it is also easy to synthesize and nontoxic. Oral administration of VNI (up to 400 mg/kg) neither leads to mortality nor reveals significant side effects up to 48 h post treatment using an experimental mouse model of acute toxicity. Trypanosomatidae CYP51 crystal structures determined in the ligand-free state and complexed with several azole inhibitors as well as a substrate analog revealed high rigidity of the CYP51 substrate binding cavity, which must be essential for the enzyme strict substrate specificity and functional conservation. Explaining profound potency of the VNI inhibitory scaffold, the structures also outline guidelines for its further development. First steps of the VNI scaffold optimization have been undertaken; the results presented here support the notion that CYP51 structure-based rational design of more efficient, pathogen-specific inhibitors represents a highly promising direction.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/15705/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALcristiane_silva_etal_IOC_2012.pdfcristiane_silva_etal_IOC_2012.pdfapplication/pdf948085https://www.arca.fiocruz.br/bitstream/icict/15705/2/cristiane_silva_etal_IOC_2012.pdf167f4d98e683569fad019aa30b70196bMD52TEXTcristiane_silva_etal_IOC_2012.pdf.txtcristiane_silva_etal_IOC_2012.pdf.txtExtracted 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| dc.title.pt_BR.fl_str_mv |
CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds |
| title |
CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds |
| spellingShingle |
CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds Hargrove, Tatiana Y. Inibição Estrutura de cristal Esteróis 14α-demethylase CYP51 Crystal structure Inhibition Sterol 14α-demethylase |
| title_short |
CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds |
| title_full |
CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds |
| title_fullStr |
CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds |
| title_full_unstemmed |
CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds |
| title_sort |
CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds |
| author |
Hargrove, Tatiana Y. |
| author_facet |
Hargrove, Tatiana Y. Kim, Kwangho Soeiro, Maria de Nazaré Correia Silva, Cristiane França da Batista, Denise da Gama Jaen Batista, Marcos Meuser Yazlovitskaya, Eugenia M. Waterman, Michael R. Sulikowski, Gary A. Lepesheva, Galina I. |
| author_role |
author |
| author2 |
Kim, Kwangho Soeiro, Maria de Nazaré Correia Silva, Cristiane França da Batista, Denise da Gama Jaen Batista, Marcos Meuser Yazlovitskaya, Eugenia M. Waterman, Michael R. Sulikowski, Gary A. Lepesheva, Galina I. |
| author2_role |
author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Hargrove, Tatiana Y. Kim, Kwangho Soeiro, Maria de Nazaré Correia Silva, Cristiane França da Batista, Denise da Gama Jaen Batista, Marcos Meuser Yazlovitskaya, Eugenia M. Waterman, Michael R. Sulikowski, Gary A. Lepesheva, Galina I. |
| dc.subject.other.pt_BR.fl_str_mv |
Inibição Estrutura de cristal Esteróis 14α-demethylase |
| topic |
Inibição Estrutura de cristal Esteróis 14α-demethylase CYP51 Crystal structure Inhibition Sterol 14α-demethylase |
| dc.subject.en.pt_BR.fl_str_mv |
CYP51 Crystal structure Inhibition Sterol 14α-demethylase |
| description |
Vanderbilt University. School of Medicine. Department of Biochemistry. Nashville, TN, USA. |
| publishDate |
2012 |
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2012 |
| dc.date.accessioned.fl_str_mv |
2016-09-06T16:23:08Z |
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2016-09-06T16:23:08Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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HARGROVE, Tatiana Y. et al. CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds. International Journal for Parasitology: Drugs and Drug Resistance, v.2, p.178–186, 2012. |
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https://www.arca.fiocruz.br/handle/icict/15705 |
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2211-3207 |
| dc.identifier.doi.none.fl_str_mv |
10.1016/j.ijpddr.2012.06.001 |
| identifier_str_mv |
HARGROVE, Tatiana Y. et al. CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds. International Journal for Parasitology: Drugs and Drug Resistance, v.2, p.178–186, 2012. 2211-3207 10.1016/j.ijpddr.2012.06.001 |
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Springer Verlag |
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Springer Verlag |
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