title: Assessment of partially deoxygenated deoxynojirimycin derivatives as glucosylceramide synthase inhibitors.
abstract: Glucosylceramide synthase (GCS) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies, including type 2 diabetes. The clinical drug N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its substrate, ceramide. In this work we demonstrate that, in contrast to what is proposed in this model, the C2-hydroxyl of the deoxynojirimycin core is important for GCS inhibition. Here we show that C6-OH appears of less important, which may set guidelines for the development of GCS inhibitors that have less affinity (in comparison with Zavesca) for other glycoprocessing enzymes, in particular those hydrolases that act on glucosylceramide.
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University , Leiden, The Netherlands.
authors.forename: Richard J B H N
authors.initials: RJ
authors.lastname: van den Berg
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University , Leiden, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Wennekes
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University , Leiden, The Netherlands.
authors.forename: Amar
authors.initials: A
authors.lastname: Ghisaidoobe
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center , Amsterdam, The Netherlands.
authors.forename: Wilma E
authors.initials: WE
authors.lastname: Donker-Koopman
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center , Amsterdam, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Strijland
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center , Amsterdam, The Netherlands.
authors.forename: Rolf G
authors.initials: RG
authors.lastname: Boot
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University , Leiden, The Netherlands.
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center , Amsterdam, The Netherlands.
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University , Leiden, The Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
keywords: Gaucher disease; Glucosylceramide synthase; ceramide; deoxynojirimycin; iminosugar