Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

Abstract

Gaucher disease is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene. Missense mutations result in reduced enzyme activity that may be due to misfolding, raising the possibility of small-molecule chaperone correction of the defect. Screening large compound libraries by quantitative high-throughput screening (qHTS) provides comprehensive information on the potency, efficacy, and structureactivity relationships (SAR) of active compounds directly from the primary screen, facilitating identification of leads for medicinal chemistry optimization. We used qHTS to rapidly identify three structural series of potent, selective, nonsugar glucocerebrosidase inhibitors. The three structural classes had excellent potencies and efficacies and, importantly, high selectivity against closely related hydrolases. Preliminary SAR data were used to select compounds with high activity in both enzyme and cell-based assays. Compounds from two of these structural series increased N370S mutant glucocerebrosidase activity by 40 -90% in patient cell lines and enhanced lysosomal colocalization, indicating chaperone activity. These small molecules have potential as leads for chaperone therapy for Gaucher disease, and this paradigm promises to accelerate the development of leads for other rare genetic disorders.probe identification ͉ structure-activity relationship ͉ small-molecule inhibitor ͉ chaperone therapy

Acid β‐glucosidase mutants linked to gaucher disease, parkinson disease, and lewy body dementia alter α‐synuclein processing

“…However, future studies will see the testing of additional GBA chaperones to determine their individual effects. 39 Interestingly, using the D409V variant of mtGBA in our PC12-SNCA cell model, we showed that the rise in cellular SNCA concentrations can be pharmacologically reversed by rapamycin. The known function of GBA combined with our rapamycin data suggest-but do not prove (given the multiple effects of mTOR inhibition)-an intralysosomal location for the observed effect of mtGBA on SNCA.…”

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

“…Cell biology studies examining the trafficking and folding of different mutant forms of the enzyme may also prove valuable. Other forms of therapy that might provide less expensive, more convenient, and possibly mutation-specific treatment of GD, such as substrate reduction, gene therapy, and small molecule chaperones, are being developed or refined [Aerts et al, 2006;Beck 2007;Sawkar et al, 2006;Sidransky et al, 2007;Zheng et al, 2007].…”

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

“…This potential for competitive antagonists/inhibitors to act as chaperones creates a role for high-throughput analysis to rapidly screen large libraries of compounds for inhibitors that could be potential pharmacological chaperones. Such screening has been successful in identifying pharmacological chaperones in lysosomal disorder and Gaucher disease studies [63,64].…”