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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.
Clin Sci (Lond) ; 124(3): 191-202, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22920224

RESUMEN

Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFß (transforming growth factor ß) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process.


Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/prevención & control , NADPH Oxidasas/antagonistas & inhibidores , Pirazoles/farmacología , Piridonas/farmacología , Albuminuria/prevención & control , Albuminuria/orina , Animales , Glucemia/análisis , Presión Sanguínea/efectos de los fármacos , Western Blotting , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/orina , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/genética , NADH NADPH Oxidorreductasas/metabolismo , NADPH Oxidasa 1 , NADPH Oxidasa 4 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Factor de Crecimiento Transformador beta/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo
3.
Drug Discov Today ; 14(9-10): 453-64, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19429504

RESUMEN

Huntington's Disease (HD) is a rare neurodegenerative disease caused by mutation of the huntingtin gene that results in a protein with an expanded stretch of glutamine repeats (polyQ). Knowledge of validated targets is in its infancy, and thus, traditional target-based drug discovery strategies are of limited use. Alternative approaches are needed, and early attempts were aimed at identifying molecules that inhibited the aggregation of polyQ huntingtin fragments. More recently, phenotypic assays were used to find molecules able to reverse some of the pathogenic mechanisms of HD. Such discovery strategies have an impact on the configuration of screening cascades for effective translation of drug candidates toward clinical trials.


Asunto(s)
Descubrimiento de Drogas/métodos , Enfermedad de Huntington/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas , Animales , Agregación Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Proteína Huntingtina , Enfermedad de Huntington/etiología , Enfermedad de Huntington/genética , Modelos Biológicos , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Análisis por Matrices de Proteínas , Transcripción Genética/efectos de los fármacos
4.
IDrugs ; 11(9): 653-60, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18763216

RESUMEN

Huntington's disease (HD) is a rare neurodegenerative disorder that progressively destroys the mental capacity and motor control of patients. This loss of motor control results in abnormal body movements (chorea) - the hallmark of HD. Given that no disease-modifying therapy for HD exists and that available symptomatic treatments are not highly efficacious, the medical need for this 'orphan' disease remains high. The number of compounds that are undergoing discovery and development for the treatment of HD has increased significantly in recent years, spurred by legislative incentives for orphan drug development and by support from non-profit foundations. Thus, hope exists for patients with HD that efficacious medicines will become available.


Asunto(s)
Diseño de Fármacos , Enfermedad de Huntington/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Drogas en Investigación/farmacología , Drogas en Investigación/uso terapéutico , Humanos , Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/fisiopatología , Fármacos Neuroprotectores/farmacología , Producción de Medicamentos sin Interés Comercial , Enfermedades Raras/tratamiento farmacológico
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