RESUMEN
Various heterocyclic hetero-methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A study of their structure-activity relationship (SAR) related to caspase-1, -3, -6, and -8 is reported. Their efficacy in a cellular model of cell death is also discussed. Potent broad-spectrum caspase inhibitors have been identified.
Asunto(s)
Inhibidores de Caspasas , Muerte Celular/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , Compuestos Heterocíclicos/farmacología , Cetonas/farmacología , Animales , Ácido Aspártico/química , Células Cultivadas , Compuestos Heterocíclicos/síntesis química , Cetonas/síntesis química , Ratones , Modelos Biológicos , Naftoles/química , Relación Estructura-Actividad , Valina/químicaRESUMEN
Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.
Asunto(s)
Inhibidores de Caspasas , Dipéptidos/síntesis química , Dipéptidos/farmacología , Apoptosis/efectos de los fármacos , Carbamatos , Línea Celular , Humanos , Concentración 50 Inhibidora , Cinética , Enfermedades Neurodegenerativas/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Various aryloxy methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A systematic study of their structure-activity relationship (SAR) related to caspases 1, 3, 6, and 8 is reported. Highly potent irreversible broad-spectrum caspase inhibitors have been identified. Their efficacy in cellular models of cell death and inflammation are also discussed.
Asunto(s)
Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: Global cerebral ischemia is associated with delayed neuronal death. Given the role of caspases in apoptosis, caspase inhibitors may provide neuronal protection after cardiac arrest. To this end, the authors generated a transgenic rat line expressing baculovirus p35, a broad-spectrum caspase inhibitor, in central neurons. Its effects were evaluated on neuronal cell death and outcome after global cerebral ischemia. METHODS: Global cerebral ischemia was induced by cardiocirculatory arrest. After 6 min, animals were resuscitated by controlled ventilation, extrathoracic cardiac massage, epinephrine, and electrical countershocks. Neuronal death was assessed after 7 days by histologic evaluation of the hippocampal cornu ammonis 1 sector. Postischemic outcome was assessed by determination of overall survival and according to neurologic deficit scores 24 h, 3 days, and 7 days after resuscitation. RESULTS: The rate of 7-day survival after cardiac arrest for the transgenic rats (85%) was significantly higher than that for the nontransgenic controls (52%; P < 0.05). However, no differences were observed either in the number of terminal deoxynucleotidyltransferase-mediated d-uracil triphosphate-biotin nick end-labeling-positive cells or viable neurons in the cornu ammonis 1 sector or in the neurologic deficit score when comparing surviving transgenic and nontransgenic rats. These findings suggest that neuronal apoptosis after cardiac arrest is not primarily initiated by activation of caspases. CONCLUSION: Expression of baculovirus p35 can improve survival after cardiac arrest in rats, but the mode and site of action remain to be elucidated.
Asunto(s)
Baculoviridae/metabolismo , Reanimación Cardiopulmonar , Inhibidores de Caspasas , Inhibidores Enzimáticos/metabolismo , Paro Cardíaco/fisiopatología , Proteínas Virales/fisiología , Animales , Animales Modificados Genéticamente , Northern Blotting , Southern Blotting , Western Blotting , Química Encefálica/genética , Isquemia Encefálica/patología , Muerte Celular/fisiología , Electrochoque , Hipocampo/patología , Hibridación in Situ , Etiquetado Corte-Fin in Situ , Proteínas Inhibidoras de la Apoptosis , Microinyecciones , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Neuronas/patología , Ratas , Ratas Wistar , Sobrevida , Proteínas Virales/biosíntesis , Proteínas Virales/genéticaRESUMEN
Presenilin is implicated in the pathogenesis of Alzheimer's disease. It is thought to constitute the catalytic subunit of the gamma-secretase complex that catalyzes intramembrane cleavage of beta-amyloid precursor protein, the last step in the generation of amyloidogenic Abeta peptides. The latter are major constituents of amyloid plaques in the brain of Alzheimer's disease patients. Inhibitors of gamma-secretase are considered potential therapeutics for the treatment of this disease because they prevent production of Abeta peptides. Recently, we discovered a family of presenilin-type aspartic proteases. The founding member, signal peptide peptidase, catalyzes intramembrane cleavage of distinct signal peptides in the endoplasmic reticulum membrane of animals. In humans, the protease plays a crucial role in the immune system. Moreover, it is exploited by the hepatitis C virus for the processing of the structural components of the virion and hence is an attractive target for anti-infective intervention. Signal peptide peptidase and presenilin share identical active site motifs and both catalyze intramembrane proteolysis. These common features let us speculate that gamma-secretase inhibitors directed against presenilin may also inhibit signal peptide peptidase. Here we demonstrate that some of the most potent known gamma-secretase inhibitors efficiently inhibit signal peptide peptidase. However, we found compounds that showed higher specificity for one or the other protease. Our findings highlight the possibility of developing selective inhibitors aimed at reducing Abeta generation without affecting other intramembrane-cleaving aspartic proteases.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Endopeptidasas/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Humanos , Especificidad por SustratoRESUMEN
A new structural class of broad spectrum caspase inhibitors was optimized for its activity against caspases 1, 3, 6, 7, and 8. The most potent compound had low nanomolar broad spectrum activity, in particular, single digit nanomolar inhibitory activity against caspase 8.