Alpha-1-C-octyl-1-deoxynojirimycin as a pharmacological chaperone for Gaucher disease.

The most common lysosomal storage disorder, Gaucher disease, is caused by inefficient folding and trafficking of certain variants of lysosomal beta-glucosidase (beta-Glu, also known as beta-glucocerebrosidase). Recently, Sawker et al. reported that the addition of subinhibitory concentrations (10 microM) of the pharmacological chaperone N-nonyl-1-deoxynojirimycin (NN-DNJ) (10) to Gaucher patient-derived cells leads to a 2-fold increase in activity of mutant (N370S) enzyme [Proc. Natl. Acad. Sci. U.S.A.2002, 99, 15428]. However, we found that the addition of NN-DNJ at 10 microM lowered the lysosomal alpha-glucosidase (alpha-Glu) activity by 50% throughout the assay period in spite of the excellent chaperoning activity in N370S fibroblasts. Hence, we prepared a series of DNJ derivatives with an alkyl chain at the C-1alpha position and evaluated their in vitro inhibitory activity and potential as pharmacological chaperones for Gaucher cell lines. Among them, alpha-1-C-octyl-DNJ (CO-DNJ) (15) showed 460-fold stronger in vitro inhibitory activity than DNJ toward beta-Glu, while NN-DNJ enhanced in vitro inhibitory activity by 360-fold. Treatment with CO-DNJ (20 microM) for 4 days maximally increased intracellular beta-Glu activity by 1.7-fold in Gaucher N370 cell line (GM0037) and by 2.0-fold in another N370 cell line (GM00852). The addition of 20 microM CO-DNJ to the N370S (GM00372) culture medium for 10 days led to 1.9-fold increase in the beta-Glu activity without affecting the intracellular alpha-Glu activity for 10 days. Only CO-DNJ showed a weak beta-Glu chaperoning activity in the L444P type 2 variant, with 1.2-fold increase at 5-20 microM, and furthermore maximally increased the alpha-Glu activity by 1.3-fold at 20 microM. These experimental results suggest that CO-DNJ is a significant pharmacological chaperone for N370S Gaucher variants, minimizing the potential for undesirable side effects such as alpha-Glu inhibition.