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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.

Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD.

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.

Synthesis and Activity of a New Series of Antileishmanial Agents.

We have determined that tetrahydroindazoles such as show potent activity against , the causative agent of leishmaniasis. While the Hsp90 activity and anticancer properties of have previously been explored, we present here our efforts to optimize their activity against 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.