Structure-activity relationships of oxysterol-derived pharmacological chaperones for Niemann-Pick type C1 protein

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 (11061T) has been shown to cause a f...

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Published inBioorganic & medicinal chemistry letters Vol. 24; no. 15; pp. 3480 - 3485
Main Authors Ohgane, Kenji, Karaki, Fumika, Noguchi-Yachide, Tomomi, Dodo, Kosuke, Hashimoto, Yuichi
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier 01.08.2014
Subjects
Carrier Proteins - antagonists & inhibitors
Carrier Proteins - genetics
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Dose-Response Relationship, Drug
Humans
Life Sciences & Biomedicine
Membrane Glycoproteins - antagonists & inhibitors
Membrane Glycoproteins - genetics
Molecular Structure
Mutation
Niemann-Pick Disease, Type C - genetics
Pharmacology & Pharmacy
Physical Sciences
Science & Technology
Sterols - chemical synthesis
Sterols - chemistry
Sterols - pharmacology
Structure-Activity Relationship
DISEASE TYPE-C
CHOLESTEROL
MEMBRANE
PHENOTYPE
PURIFIED NPC1 PROTEIN
Structure-activity relationships
Pharmacological chaperone
STEROL-BINDING
NPC1
HUMAN P-GLYCOPROTEIN
CELL-MIGRATION
Oxysterol
ENDOPLASMIC-RETICULUM
Niemann-Pick disease type C
ALPHA-GALACTOSIDASE
Niemann–Pick disease type C
Structure–activity relationships
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Summary: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 (11061T) 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(11061T) 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(11061T) mutant. (C) 2014 Elsevier Ltd. All rights reserved.
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ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.05.064