title: FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Helliwell
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Karkare
authors.affiliation: Institut de Biologie Moléculaire des Plantes, CNRS, Unité Propre de Recherche 2357, Strasbourg cedex 67083, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Bergdoll
authors.affiliation: Institut de Biologie Moléculaire des Plantes, CNRS, Unité Propre de Recherche 2357, Strasbourg cedex 67083, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Rahier
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Juliet R
authors.initials: JR
authors.lastname: Leighton-Davis
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Fioretto
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Aust
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Ireos
authors.initials: I
authors.lastname: Filipuzzi
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Mathias
authors.initials: M
authors.lastname: Frederiksen
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts, 02139, USA.
authors.forename: John
authors.initials: J
authors.lastname: Gounarides
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Pierre-Eloi
authors.initials: PE
authors.lastname: Imbert
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Jeker
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Knochenmuss
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Krastel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Anais
authors.initials: A
authors.lastname: Margerit
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Klaus
authors.initials: K
authors.lastname: Memmert
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Charlotte V
authors.initials: CV
authors.lastname: Miault
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Rao Movva
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Alban
authors.initials: A
authors.lastname: Muller
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Naegeli
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Oberer
authors.affiliation: GNF, San Diego, California 92121, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Prindle
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Riedl
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Schuierer
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts, 02139, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Sexton
authors.affiliation: GNF, San Diego, California 92121, USA.
authors.forename: Jianshi
authors.initials: J
authors.lastname: Tao
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts, 02139, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Roggo
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Reinker
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel, CH-4056, Switzerland.
authors.forename: Christian N
authors.initials: CN
authors.lastname: Parker
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000935:Antifungal Agents / Q000737:chemistry*; D002176:Candida albicans; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry; D025141:Drug Resistance, Fungal / Q000235:genetics; D004875:Ergosterol / Q000096:biosynthesis; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000935:Antifungal Agents; C487953:FR171456; D029701:Saccharomyces cerevisiae Proteins; D002784:Cholesterol; D015096:3-Hydroxysteroid Dehydrogenases; C069942:ERG26 protein, S cerevisiae; D004875:Ergosterol