FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p.

Autor:	Helliwell SB; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Karkare S; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Bergdoll M; Institut de Biologie Moléculaire des Plantes, CNRS, Unité Propre de Recherche 2357, Strasbourg cedex 67083, France., Rahier A; Institut de Biologie Moléculaire des Plantes, CNRS, Unité Propre de Recherche 2357, Strasbourg cedex 67083, France., Leighton-Davis JR; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Fioretto C; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Aust T; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Filipuzzi I; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Frederiksen M; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Gounarides J; Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts, 02139, USA., Hoepfner D; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Hofmann A; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Imbert PE; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Jeker R; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Knochenmuss R; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Krastel P; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Margerit A; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Memmert K; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Miault CV; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Rao Movva N; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Muller A; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Naegeli HU; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Oberer L; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Prindle V; GNF, San Diego, California 92121, USA., Riedl R; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Schuierer S; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Sexton JA; Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts, 02139, USA., Tao J; GNF, San Diego, California 92121, USA., Wagner T; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Yin H; Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts, 02139, USA., Zhang J; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Roggo S; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Reinker S; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland., Parker CN; Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2015 Oct 12; Vol. 6, pp. 8613. Date of Electronic Publication: 2015 Oct 12.
DOI:	10.1038/ncomms9613
Abstrakt:	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.
Databáze:	MEDLINE
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