2 research outputs found
siRNA screen identifies QPCT as a druggable target for Huntington's disease.
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
Novel Hits in the Correction of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein: Synthesis, Pharmacological, and ADME Evaluation of Tetrahydropyrido[4,3‑<i>d</i>]pyrimidines for the Potential Treatment of Cystic Fibrosis
Cystic fibrosis (CF) is a lethal
genetic disease caused by mutations
of the gene encoding the cystic fibrosis transmembrane conductance
regulator (CFTR) with a prevalence of the ΔF508 mutation. Whereas
the detailed mechanisms underlying disease have yet to be fully elucidated,
recent breakthroughs in clinical trials have demonstrated that CFTR
dysfunction can be corrected by drug-like molecules. On the basis
of this success, a screening campaign was carried out, seeking new
drug-like compounds able to rescue ΔF508-CFTR that led to the
discovery of a novel series of correctors based on a tetrahydropyridoÂ[4,3-<i>d</i>]Âpyrimidine core. These molecules proved to be soluble,
cell-permeable, and active in a disease relevant functional-assay.
The series was then further optimized with emphasis on biological
data from multiple cell systems while keeping physicochemical properties
under strict control. The pharmacological and ADME profile of this
corrector series hold promise for the development of more efficacious
compounds to be explored for therapeutic use in CF