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1.
Nat Chem Biol ; 11(5): 347-354, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25848931

RESUMEN

Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. We focused on glutaminyl cyclase (QPCT), which had one of the strongest effects on mutant HTT-induced toxicity and aggregation in the cell-based siRNA screen and also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone αB-crystallin and reduced the aggregation of diverse proteins. We generated new QPCT inhibitors using in silico methods followed by in vitro screening, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development.


Asunto(s)
Aminoaciltransferasas/efectos de los fármacos , Aminoaciltransferasas/genética , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/genética , ARN Interferente Pequeño , Aminoaciltransferasas/antagonistas & inhibidores , Animales , Células Cultivadas , Biología Computacional , Drosophila , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Proteína Huntingtina , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Pez Cebra , Cadena B de alfa-Cristalina/metabolismo
2.
J Infect Dis ; 205(8): 1278-86, 2012 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-22396598

RESUMEN

Plasmodium parasites undergo a clinically silent and obligatory developmental phase in the host's liver cells before they are able to infect erythrocytes and cause malaria symptoms. To overcome the scarcity of compounds targeting the liver stage of malaria, we screened a library of 1037 existing drugs for their ability to inhibit Plasmodium hepatic development. Decoquinate emerged as the strongest inhibitor of Plasmodium liver stages, both in vitro and in vivo. Furthermore, decoquinate kills the parasite's replicative blood stages and is active against developing gametocytes, the forms responsible for transmission. The drug acts by selectively and specifically inhibiting the parasite's mitochondrial bc(1) complex, with little cross-resistance with the antimalarial drug atovaquone. Oral administration of a single dose of decoquinate effectively prevents the appearance of disease, warranting its exploitation as a potent antimalarial compound.


Asunto(s)
Antimaláricos/farmacología , Hepatocitos/parasitología , Malaria/tratamiento farmacológico , Malaria/parasitología , Plasmodium/efectos de los fármacos , Animales , Atovacuona/farmacología , Línea Celular Tumoral , Decoquinato/farmacología , Evaluación Preclínica de Medicamentos/métodos , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Modelos Moleculares , Estructura Molecular , Conformación Proteica
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