Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 27, Issue 12, Pages 2781-2787Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.04.062
Keywords
Niemann-Pick disease type C; NPC1; Non-steroidal pharmacological chaperone; Structure-activity relationships
Categories
Funding
- JSPS KAKENHI [2210583, 22249006]
- Grants-in-Aid for Scientific Research [22249006, 25293027, 17K15487, 15K08015, 17H03996] Funding Source: KAKEN
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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. (C) 2017 Elsevier Ltd. All rights reserved.
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