Structure-activity relationships of oxysterol-derived pharmacological chaperones for Niemann-Pick type C1 protein
- Bioorg Med Chem Lett. 2014 Aug 1;24(15):3480-5. doi: 10.1016/j.bmcl.2014.05.064.
- 1. 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: [email protected].
- 2. Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
- 3. RIKEN, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan.
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.