2. Academic Validation
  3. Structure-activity relationships of oxysterol-derived pharmacological chaperones for Niemann-Pick type C1 protein

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.
Kenji Ohgane 1,  Fumika Karaki 2,  Tomomi Noguchi-Yachide 2,  Kosuke Dodo 3,  Yuichi Hashimoto 2
Affiliations

Affiliations

  • 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: ohgane@me.com.
  • 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.
PMID: 24928400 DOI: 10.1016/j.bmcl.2014.05.064
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.

Keywords

NPC1; Niemann–Pick disease type C; Oxysterol; Pharmacological chaperone; Structure–activity relationships.

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