cholenic-acid-dimethylamide and Niemann-Pick-Disease--Type-C

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.

Topics: Carrier Proteins; Dose-Response Relationship, Drug; Humans; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins; Molecular Structure; Mutation; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Sterols; Structure-Activity Relationship