Dataset for: Image-based screen capturing misfolding status of Niemann-Pick type C1 identifies potential candidates for chaperone drugs

Niemann-Pick disease type C is a rare, fatal neurodegenerative disorder characterized by massive intracellular accumulation of cholesterol. In most cases, loss-of-function mutations in NPC1 gene that encodes for a lysosomal cholesterol transporter NPC1 are responsible for the disease, and more than half of the mutations are considered to interfere with biogenesis or folding of the protein. Previously we have identified a series of oxysterol derivatives and phenanthridine-6-one derivatives as pharmacological chaperones, small molecules that rescue folding defective phenotypes of a mutated NPC1, and opened an avenue to develop chaperone therapy for Niemann-Pick disease type C. Here, we established an improved image-based screen for NPC1 chaperones and performed drug-repurposing screening to identify some azole antifungals, including itraconazole and posaconazole, and a kinase inhibitor lapatinib as probable pharmacological chaperones. Photo-crosslinking probes of the compounds allowed us to detect direct binding of itraconazole to a representative folding-defective mutant, NPC1-I1061T. Competitive photo-crosslinking experiments suggested that oxysterol-based chaperones and itraconazole share the same or nearby binding site(s), and sensitivity of the crosslinking to P691S mutation on the sterol-sensing domain supported currently proposed hypothesis that their binding sites are located near the domain. Although the azoles were less effective in reducing cholesterol accumulation than the oxysterol-derived chaperone or an HDAC inhibitor LBH-589, our findings should offer new starting points for developing better pharmacological chaperones for NPC1 through medicinal chemistry efforts.