ABSTRACT
The accumulation and aggregation of the microtubule-associated protein tau (tau) into intracellular neuronal tangles are a hallmark of a range of progressive neurodegenerative tauopathies, including Alzheimer's disease (AD), frontotemporal dementia, Pick's disease, and progressive supranuclear palsy. The aberrant phosphorylation of tau is associated with tau aggregates in AD. Members of the heat shock protein 70 kDa (Hsp70) family of chaperones bind directly to tau and modulate tau clearance and aggregation. Small molecules that inhibit the Hsp70 family of chaperones have been shown to reduce the accumulation of tau, including phosphorylated tau. Here, eight analogs of the rhodacyanine inhibitor, JG-98, were synthesized and evaluated. Like JG-98, many of the compounds inhibited ATPase activity of the cytosolic heat shock cognate 70 protein (Hsc70) and reduced total, aggregated, and phosphorylated tau accumulation in cultured cells. Three compounds, representing divergent clogP values, were evaluated for in vivo blood-brain barrier penetration and tau reduction in an ex vivo brain slice model. AL69, the compound with the lowest clogP and the lowest membrane retention in a parallel artificial membrane permeability assay (PAMPA), reduced phosphorylated tau accumulation. Our results suggest that benzothiazole substitutions of JG-98 that increase hydrophilicity may increase the efficacy of these Hsp70 inhibitors to reduce phosphorylated tau.
Subject(s)
Alzheimer Disease , Tauopathies , Humans , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Benzothiazoles/pharmacology , HSP70 Heat-Shock Proteins , Molecular Chaperones , tau Proteins/metabolism , Tauopathies/metabolismABSTRACT
Genetic and epigenetic alterations in FK506-binding protein 5 ( FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression.
Subject(s)
Benztropine/pharmacology , Depression/drug therapy , HSP90 Heat-Shock Proteins/metabolism , Receptors, Glucocorticoid/metabolism , Stress Disorders, Post-Traumatic/drug therapy , Tacrolimus Binding Proteins/metabolism , Animals , Benztropine/chemistry , Brain/drug effects , Brain/metabolism , Cells, Cultured , Depression/metabolism , Drug Discovery , Humans , Mice , Molecular Targeted Therapy , Protein Binding/drug effects , Stress Disorders, Post-Traumatic/metabolism , Tacrolimus Binding Proteins/antagonists & inhibitorsABSTRACT
We have determined that tetrahydroindazoles such as 1 show potent activity against Leishmania donovani, the causative agent of leishmaniasis. While the Hsp90 activity and anticancer properties of 1 have previously been explored, we present here our efforts to optimize their activity against L. donovani via the synthesis of novel analogues designed to probe the hydrophobic pocket of the protozoan Hsp90 orthologue, specifically through the auspices of functionalization of an amine embedded into the scaffold.
ABSTRACT
La Universidad El Bosque basada en el modelo biopsicosocial ha diseñado un perfil ocupacional y profesional para formar sus odontólogos con alto nivel científico y ético, capaces de generar conocimiento y desempeñarse profesionalmente basada en el modelo biopsicosocial ha diseñado un perfil ocupacional y profesional para formar a sus Odontólogos con alto nivel científico y ético, capaces de generar conocimiento y desempeñarse profesionalmente entendiendo las dinámicas y hechos de la actual sociedad y de esta manera contribuir a la solución de los problemas de la salud oral de los colombianos. Con el fin de conocer los criterios con los cuales los usuarios de servicios evalúan la calidad de los odontólogos y la coherencia que existe entre esos atributos con las características que forman parte del perfil ocupacional y profesional de los egresados de la Universidad El Bosque, se realizó este proceso de investigación cualitativo cuyos resultados aportaron al proceso de autoevaluación, a la retroalimentación del currículo y como parte del proceso de acreditación al que decidió acogerse voluntariamente esta institución de educación superior. El propósito de este estudio fue identificar los atributos por medio de los cuales los usuarios de servicios de salud evalúan el posicionamiento (imagen y lugar que ocupan) de los Odontólogos para posteriormente comparar si esos atributos coinciden con los criterios que componen el diseño del perfil esperado por parte de la institución para los egresados de la facultad de Odontología y la calificación que de acuerdo a esos atributos hacen de ellos los usuarios de sus servicios, colegas, empleados y empleadores, con el fin de fortalecer el sello distintivo que da el modelo psicosocial propuesto por la Universidad El Bosque y para responderle coherentemente y con alta competitividad a las necesidades y deseos insatisfechos de los usuarios del sector de salud de nuestro país.
