Phenanthridin-6-one derivatives as the first class of non-steroidal pharmacological chaperones for Niemann-Pick disease type C1 protein

Hiromitsu Fukuda, Fumika Karaki, Kosuke Dodo, Tomomi Noguchi-Yachide, Minoru Ishikawa, Yuichi Hashimoto, Kenji Ohgane

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Niemann-Pick disease type C is a fatal, progressive neurodegenerative disease mostly caused by mutations in Nieamnn-Pick type C1 (NPC1), a late endosomal membrane protein that is essential for intracellular cholesterol transport. The most prevalent mutation, I1061T (Ile to Thr), interferes with the protein folding process. Consequently, mutated but intrinsically functional NPC1 proteins are prematurely degraded via proteasome, leading to loss of NPC1 function. Previously, we reported sterol derivatives as pharmacological chaperones for NPC1, and showed that these derivatives can normalize folding-defective phenotypes of I1061T NPC1 mutant by directly binding to, and stabilizing, the protein. Here, we report a series of compounds containing a phenanthridin-6-one scaffold as the first class of non-steroidal pharmacological chaperones for NPC1. We also examined their structure-activity relationships.

Original languageEnglish
Pages (from-to)2781-2787
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number12
DOIs
Publication statusPublished - 2017
Externally publishedYes

Keywords

  • NPC1
  • Niemann-Pick disease type C
  • Non-steroidal pharmacological chaperone
  • Structure-activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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