Structure–activity relationship studies of Niemann-Pick type C1-like 1 (NPC1L1) ligands identified by screening assay monitoring pharmacological chaperone effect

Karaki, Fumika; Ohgane, Kenji; Dodo, Kosuke; Hashimoto, Yuichi

doi:10.1016/j.bmc.2013.06.022

Cited by 13 publications

(8 citation statements)

References 42 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ezetimibe, which binds to the second extracellular loop [12] , did not exhibit such activity ( S4 Fig . ), as previously reported [18] . These results suggest that the primary binding site of fomiroid A is not the ezetimibe-binding site in the second extracellular loop or the cholesterol-binding site in the NTD, but rather the second sterol-binding site.…”

Section: Discussionsupporting

confidence: 80%

“…Several steroidal and non-steroidal compounds, which bind to NPC1L1, have pharmacological chaperone activities that correct trafficking defects of NPC1L1 mutants. Recently, it was reported that such compounds bind to sites distinct from both the NTD and the ezetimibe-binding site [18] , [19] . To determine whether fomiroid A directly binds to hNPC1L1, we analyzed the pharmacological chaperone activity of this compound on trafficking of the L1072T/L1168I mutant to the plasma membrane.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds that bind to the second sterol-binding site of NPC1L1, which is distinct from both the NTD and the ezetimibe-binding site, exhibit pharmacological chaperone activity against the NPC1L1 L1072T/L1168I mutant. Normally, this mutant localizes predominantly to the ER, but these pharmacological chaperones re-localize it to the plasma membrane [18] , [19] . We examined the pharmacological chaperone activity of fomiroid A by confocal microscopy ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Several steroidal and non-steroidal compounds have pharmacological chaperone activities that correct trafficking defects of NPC1L1 mutants. Recently, Karaki et al reported that such compounds bind to sites distinct from both the NTD and the ezetimibe-binding site, suggesting the existence of a second sterol-binding site in NPC1L1 [18] , [19] .…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Fomiroid A, a Novel Compound from the Mushroom Fomitopsis nigra, Inhibits NPC1L1-Mediated Cholesterol Uptake via a Mode of Action Distinct from That of Ezetimibe

et al. 2014

View full text Add to dashboard Cite

Hypercholesterolemia is one of the key risk factors for coronary heart disease, a major cause of death in developed countries. Suppression of NPC1L1-mediated dietary and biliary cholesterol absorption is predicted to be one of the most effective ways to reduce the risk of hypercholesterolemia. In a screen for natural products that inhibit ezetimibe glucuronide binding to NPC1L1, we found a novel compound, fomiroid A, in extracts of the mushroom Fomitopsis nigra. Fomiroid A is a lanosterone derivative with molecular formula C30H48O3. Fomiroid A inhibited ezetimibe glucuronide binding to NPC1L1, and dose-dependently prevented NPC1L1-mediated cholesterol uptake and formation of esterified cholesterol in NPC1L1-expressing Caco2 cells. Fomiroid A exhibited a pharmacological chaperone activity that corrected trafficking defects of the L1072T/L1168I mutant of NPC1L1. Because ezetimibe does not have such an activity, the binding site and mode of action of fomiroid A are likely to be distinct from those of ezetimibe.

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Fomiroid A, a Novel Compound from the Mushroom Fomitopsis nigra, Inhibits NPC1L1-Mediated Cholesterol Uptake via a Mode of Action Distinct from That of Ezetimibe

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Recently, we revealed that NPC1L1, a cholesterol uptake transporter expressed on the luminal membrane in the intestine, functions as a modulator of warfarin therapy by regulating intestinal absorption of dietary vitamin K1 in addition to cholesterol. 8 Based on the fact that prednisolone is a steroid compound and that some steroid compounds, including cholesterol and plant sterols, have been reported to affect the expression and/or transport activity of NPC1L1, [19][20][21][22] we hypothesized that prednisolone may affect NPC1L1-mediated vitamin K1 uptake and/or NPC1L1 expression. To test this possibility, we conducted a series of in vitro experiments.…”

Section: Warfarin-related Ddismentioning

confidence: 99%

Clinical Importance of Drug-Drug Interaction Between Warfarin and Prednisolone and Its Potential Mechanism in Relation to the Niemann-Pick C1-Like 1-Mediated Pathway

Ito

Yamanashi

Takada

et al. 2019

Circ J

View full text Add to dashboard Cite

Background: Warfarin is an anticoagulant drug used to prevent thromboembolic disorders, but its pharmacological effect is affected by co-administered drugs. Therefore, careful management of warfarin-related drug-drug interactions (DDIs) is necessary for its safety and effectiveness. Recently, intestinal vitamin K1 absorption through the Niemann-Pick C1-like 1 (NPC1L1)-mediated pathway was found to affect the pharmacological effect of warfarin. This study aimed to identify high-frequency warfarin-related DDIs in a clinical setting and elucidate their mechanism(s) in terms of changes in NPC1L1 expression and/or activity. Methods and Results: Prednisolone was the most frequently suspected drug in retrospective surveys of medical records of patients who experienced warfarin-related DDIs. Prednisolone significantly increased the international normalized ratio of prothrombin time (PT-INR) values in warfarin-treated patients. To demonstrate the involvement of NPC1L1 in warfarin-prednisolone DDI, we conducted an in vitro vitamin K1 uptake assay using NPC1L1-overexpressing cells and found that prednisolone inhibited NPC1L1-mediated vitamin K1 uptake. Additionally, we found that prednisolone downregulates NPC1L1 in a glucocorticoid receptor α-dependent manner. Conclusions: Co-administration of warfarin and prednisolone frequently enhanced the anticoagulant effect of warfarin in a clinical setting. Prednisolone-mediated suppression of NPC1L1 expression and activity could be the mechanism of DDI between warfarin and prednisolone. To manage warfarin therapy, the potential of concomitant drugs to change its anticoagulant effect through NPC1L1-related mechanisms merits consideration.

show abstract

Structure–activity relationship study of non-steroidal NPC1L1 ligands identified through cell-based assay using pharmacological chaperone effect as a readout

Karaki

Ohgane

Fukuda

et al. 2014

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Structure–activity relationship studies of Niemann-Pick type C1-like 1 (NPC1L1) ligands identified by screening assay monitoring pharmacological chaperone effect

Cited by 13 publications

References 42 publications

Fomiroid A, a Novel Compound from the Mushroom Fomitopsis nigra, Inhibits NPC1L1-Mediated Cholesterol Uptake via a Mode of Action Distinct from That of Ezetimibe

Fomiroid A, a Novel Compound from the Mushroom Fomitopsis nigra, Inhibits NPC1L1-Mediated Cholesterol Uptake via a Mode of Action Distinct from That of Ezetimibe

Clinical Importance of Drug-Drug Interaction Between Warfarin and Prednisolone and Its Potential Mechanism in Relation to the Niemann-Pick C1-Like 1-Mediated Pathway

Structure–activity relationship study of non-steroidal NPC1L1 ligands identified through cell-based assay using pharmacological chaperone effect as a readout

Contact Info

Product

Resources

About