The most common lysosomal storage disorder, Gaucher disease, is caused by inefficient folding and trafficking of certain variants of lysosomal β-glucosidase (β-Glu, also known as β-glucocerebrosidase). Recently, Sawker et al. reported that the addition of subinhibitory concentrations ...
The most common lysosomal storage disorder, Gaucher disease, is caused by inefficient folding and trafficking of certain variants of lysosomal β-glucosidase (β-Glu, also known as β-glucocerebrosidase). Recently, Sawker et al. reported that the addition of subinhibitory concentrations (10μM) 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 10μM lowered the lysosomal α-glucosidase (α-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-1α position and evaluated their in vitro inhibitory activity and potential as pharmacological chaperones for Gaucher cell lines. Among them, α-1-C-octyl-DNJ (CO-DNJ) (15) showed 460-fold stronger in vitro inhibitory activity than DNJ toward β-Glu, while NN-DNJ enhanced in vitro inhibitory activity by 360-fold. Treatment with CO-DNJ (20μM) for 4 days maximally increased intracellular β-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 20μM CO-DNJ to the N370S (GM00372) culture medium for 10 days led to 1.9-fold increase in the β-Glu activity without affecting the intracellular α-Glu activity for 10 days. Only CO-DNJ showed a weak β-Glu chaperoning activity in the L444P type 2 variant, with 1.2-fold increase at 5-20μM, and furthermore maximally increased the α-Glu activity by 1.3-fold at 20μM. 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 α-Glu inhibition.
The most common lysosomal storage disorder, Gaucher disease, is caused by inefficient folding and trafficking of certain variants of lysosomal β-glucosidase (β-Glu, also known as β-glucocerebrosidase). Recently, Sawker et al. reported that the addition of subinhibitory concentrations (10μM) 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 10μM lowered the lysosomal α-glucosidase (α-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-1α position and evaluated their in vitro inhibitory activity and potential as pharmacological chaperones for Gaucher cell lines. Among them, α-1-C-octyl-DNJ (CO-DNJ) (15) showed 460-fold stronger in vitro inhibitory activity than DNJ toward β-Glu, while NN-DNJ enhanced in vitro inhibitory activity by 360-fold. Treatment with CO-DNJ (20μM) for 4 days maximally increased intracellular β-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 20μM CO-DNJ to the N370S (GM00372) culture medium for 10 days led to 1.9-fold increase in the β-Glu activity without affecting the intracellular α-Glu activity for 10 days. Only CO-DNJ showed a weak β-Glu chaperoning activity in the L444P type 2 variant, with 1.2-fold increase at 5-20μM, and furthermore maximally increased the α-Glu activity by 1.3-fold at 20μM. 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 α-Glu inhibition.
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