FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p

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Helliwell, SB
Karkare, S
Bergdoll, M
Rahier, A
Leighton-Davis, JR
Fioretto, C
Aust, T
Filipuzzi, I
Frederiksen, M
Gounarides, J
Hoepfner, D
Hofmann, A
Imbert, PE
Jeker, R
et al.
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2015
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http://creativecommons.org/licenses/by/4.0/
Abstract

FR171456 is a natural product with cholesterol-lowering properties in animal models, but its molecular target is unknown, which hinders further drug development. Here we show that FR171456 specifically targets the sterol-4-alpha-carboxylate-3-dehydrogenase (Saccharomyces cerevisiae—Erg26p, Homo sapiens—NSDHL (NAD(P) dependent steroid dehydrogenase-like)), an essential enzyme in the ergosterol/cholesterol biosynthesis pathway. FR171456 significantly alters the levels of cholesterol pathway intermediates in human and yeast cells. Genome-wide yeast haploinsufficiency profiling experiments highlight the erg26/ERG26 strain, and multiple mutations in ERG26 confer resistance to FR171456 in growth and enzyme assays. Some of these ERG26 mutations likely alter Erg26 binding to FR171456, based on a model of Erg26. Finally, we show that FR171456 inhibits an artificial Hepatitis C viral replicon, and has broad antifungal activity, suggesting potential additional utility as an anti-infective. The discovery of the target and binding site of FR171456 within the target will aid further development of this compound.

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Nature Communications
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6
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1
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© The Author(s) 2015. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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Helliwell, et al., FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p, Nature Communications, 2015, 6 (1)
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