title: Structure-activity relationships of oxysterol-derived pharmacological chaperones for Niemann-Pick type C1 protein.
abstract: Niemann-Pick disease type C is a fatal neurodegenerative disease, and its major cause is mutations in NPC1 gene. This gene encodes NPC1 protein, a late endosomal polytopic membrane protein required for intracellular cholesterol trafficking. One prevalent mutation (I1061T) has been shown to cause a folding defect, which results in failure of endosomal localization of the protein, leading to loss-of-function phenotype. We have previously demonstrated that several oxysterols and their derivatives act as pharmacological chaperones; binding of these compounds to NPC1(I1061T) mutant protein corrects the localization/maturation defect of the mutant protein. Here, we disclose detailed structure-activity relationships of oxysterol derivatives as pharmacological chaperones for NPC1(I1061T) mutant.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; RIKEN, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan. Electronic address: ohgane@me.com.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohgane
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Fumika
authors.initials: F
authors.lastname: Karaki
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Noguchi-Yachide
authors.affiliation: RIKEN, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Dodo
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D015394:Molecular Structure; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics; D013261:Sterols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D013261:Sterols
keywords: NPC1; Niemann–Pick disease type C; Oxysterol; Pharmacological chaperone; Structure–activity relationships