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Pesquisa : D08.244.453.878 [Categoria DeCS]
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[PMID]:28651982
[Au] Autor:Yates CM; Garvey EP; Shaver SR; Schotzinger RJ; Hoekstra WJ
[Ad] Endereço:Viamet Pharmaceuticals Inc., Durham, NC 27703, USA. Electronic address: cyates@viamet.com.
[Ti] Título:Design and optimization of highly-selective, broad spectrum fungal CYP51 inhibitors.
[So] Source:Bioorg Med Chem Lett;27(15):3243-3248, 2017 08 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:While the orally-active azoles such as fluconazole and posaconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug-drug interactions, liver, and reproductive toxicities). Recently we described the rationally-designed, antifungal agent VT-1161 that is more selective for fungal CYP51 than related human CYP enzymes such as CYP3A4. Herein, we describe the use of a homology model of Aspergillus fumigatus to design and optimize a novel series of highly selective, broad spectrum fungal CYP51 inhibitors. This series includes the oral antifungal VT-1598 that exhibits excellent potency against yeast, dermatophyte, and mold fungal pathogens.
[Mh] Termos MeSH primário: Inibidores de 14-alfa Desmetilase/química
Inibidores de 14-alfa Desmetilase/farmacologia
Antifúngicos/química
Antifúngicos/farmacologia
Azóis/química
Azóis/farmacologia
Fungos/enzimologia
[Mh] Termos MeSH secundário: Aspergilose/tratamento farmacológico
Aspergilose/microbiologia
Aspergillus fumigatus/efeitos dos fármacos
Aspergillus fumigatus/enzimologia
Família 51 do Citocromo P450/antagonistas & inibidores
Família 51 do Citocromo P450/metabolismo
Desenho de Drogas
Fungos/efeitos dos fármacos
Seres Humanos
Simulação de Acoplamento Molecular
Micoses/tratamento farmacológico
Micoses/microbiologia
Piridinas/química
Piridinas/farmacologia
Tetrazóis/química
Tetrazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (14-alpha Demethylase Inhibitors); 0 (Antifungal Agents); 0 (Azoles); 0 (Pyridines); 0 (Tetrazoles); 0 (VT-1161); EC 1.14.13.70 (Cytochrome P450 Family 51)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE


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[PMID]:27359265
[Au] Autor:Klosowski AC; Brahm L; Stammler G; De Mio LL
[Ad] Endereço:First and fourth authors: Universidade Federal do Paraná, Rua dos Funcionários 1540, 80035-050 Curitiba, Brazil; second and third authors: BASF SE, Fungicide Research, Agricultural Center Limburgerhof, D-67117, Germany.
[Ti] Título:Competitive Fitness of Phakopsora pachyrhizi Isolates with Mutations in the CYP51 and CYTB Genes.
[So] Source:Phytopathology;106(11):1278-1284, 2016 11.
[Is] ISSN:0031-949X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Soybean rust (Phakopsora pachyrhizi) in Brazil is mainly controlled with applications of fungicides, including demethylation inhibitors (DMI) and quinone outside inhibitors (QoI). Isolates with less sensitivity to DMI and QoI have been reported, and these have been found to have mutations in the CYP51 and CYTB genes, respectively. There have been no reports of fitness costs in isolates with mutations in CYP51 and CYTB, and the aim of this work was to compare the competitive ability of isolates with lower DMI or QoI sensitivities with that of sensitive (wild-type) isolates. Urediniospores of sensitive wild-type isolates and isolates with different CYP51 or CYTB alleles were mixed and inoculated on detached soybean leaves. After 3 weeks, urediniospores were harvested and used as inoculum for the next disease cycle. Frequencies of relevant target site mutations were monitored using the pyrosequencing method over four disease cycles. Isolates with lower DMI sensitivity and different CYP51 alleles had competitive disadvantages compared with a DMI-sensitive, wild-type CYP51 isolate. In contrast, the isolate with the F129L mutation in the CYTB gene competed equally well with a QoI-sensitive, wild-type CYTB isolate under the conditions of this experiment. The CYP51 and CYTB alleles were stable in all isolates over four disease cycles when cultivated alone.
[Mh] Termos MeSH primário: Família 51 do Citocromo P450/genética
Citocromos b/genética
Farmacorresistência Fúngica/genética
Phakopsora pachyrhizi/fisiologia
Doenças das Plantas/microbiologia
Feijão de Soja/microbiologia
[Mh] Termos MeSH secundário: Alelos
Substituição de Aminoácidos
Brasil
Proteínas Fúngicas/genética
Fungicidas Industriais/farmacologia
Genótipo
Mutação
Phakopsora pachyrhizi/genética
Análise de Sequência de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fungal Proteins); 0 (Fungicides, Industrial); 9035-37-4 (Cytochromes b); EC 1.14.13.70 (Cytochrome P450 Family 51)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170629
[Lr] Data última revisão:
170629
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160701
[St] Status:MEDLINE



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