title: Alpha-1-C-octyl-1-deoxynojirimycin as a pharmacological chaperone for Gaucher disease.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan.
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ikeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.forename: Guillaume
authors.initials: G
authors.lastname: Godin
authors.forename: Philippe
authors.initials: P
authors.lastname: Compain
authors.forename: Olivier
authors.initials: O
authors.lastname: Martin
authors.forename: Naoki
authors.initials: N
authors.lastname: Asano
mesh_terms: D017485:1-Deoxynojirimycin / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005776:Gaucher Disease / Q000188:drug therapy* / Q000473:pathology; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones; D018716:Molecular Mimicry; D013329:Structure-Activity Relationship
chemical_list: D018832:Molecular Chaperones; C501633:deoxynojirimycine; D017485:1-Deoxynojirimycin; D005962:Glucosylceramidase; D005944:Glucosamine