NCGC607

A review.Gaucher disease (GD) is a lysosomal storage disorder (LSD), mutations in both alleles of the GBA1 gene result in deficient glucocerebrosidase (GCase) activity, which in turn leads to the accumulation of glycolipid substrates and impaired lysosomal function.In addition to its role in the rare disorder GD, mutations in GBA1 are the most frequent known genetic risk factor for the common complex disorder Parkinson's disease (PD), PD patients are 2-31% more likely to carry a mutation in GBA1 than matched controls, and there appears to be a reciprocal relationship between levels of GCase and levels of the aggregate-prone protein alpha-synuclein.To enhance the development of new therapeutics targeting GCase, induced human pluripotent stem cell (iPSC)-derived models are established to test the efficacy of new therapeutic strategies.Very recently, two novel small-mol. non-inhibitory chaperones of GCase, NCGC758 and NCGC607, were evaluated in such models with promising results, and the perspective commentary briefly discussed relative study work.

Mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), cause Gaucher disease (GD) and are the most common genetic risk factor for Parkinson’s disease (PD). Pharmacological chaperones (PCs) are being developed as an alternative treatment approach for GD and PD. To date, NCGC00241607 (NCGC607) is one of the most promising PCs. Using molecular docking and molecular dynamics simulation we identified and characterized six allosteric binding sites on the GCase surface suitable for PCs. Two sites were energetically more preferable for NCGC607 and located nearby to the active site of the enzyme. We evaluated the effects of NCGC607 treatment on GCase activity and protein levels, glycolipids concentration in cultured macrophages from GD (n = 9) and GBA-PD (n = 5) patients as well as in induced human pluripotent stem cells (iPSC)—derived dopaminergic (DA) neurons from GBA-PD patient. The results showed that NCGC607 treatment increased GCase activity (by 1.3-fold) and protein levels (by 1.5-fold), decreased glycolipids concentration (by 4.0-fold) in cultured macrophages derived from GD patients and also enhanced GCase activity (by 1.5-fold) in cultured macrophages derived from GBA-PD patients with N370S mutation (p < 0.05). In iPSC-derived DA neurons from GBA-PD patients with N370S mutation NCGC607 treatment increased GCase activity and protein levels by 1.1-fold and 1.7-fold (p < 0.05). Thus, our results showed that NCGC607 could bind to allosteric sites on the GCase surface and confirmed its efficacy on cultured macrophages from GD and GBA-PD patients as well as on iPSC-derived DA neurons from GBA-PD patients.