FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p

Stephen B. Helliwell (), Shantanu Karkare, Marc Bergdoll, Alain Rahier, Juliet R. Leighton-Davis, Celine Fioretto, Thomas Aust, Ireos Filipuzzi, Mathias Frederiksen, John Gounarides, Dominic Hoepfner, Andreas Hofmann, Pierre-Eloi Imbert, Rolf Jeker, Richard Knochenmuss, Philipp Krastel, Anais Margerit, Klaus Memmert, Charlotte V. Miault, N. Rao Movva, Alban Muller, Hans-Ulrich Naegeli, Lukas Oberer, Vivian Prindle, Ralph Riedl, Sven Schuierer, Jessica A. Sexton, Jianshi Tao, Trixie Wagner, Hong Yin, Juan Zhang, Silvio Roggo, Stefan Reinker and Christian N. Parker
Additional contact information
Stephen B. Helliwell: Novartis Institutes for BioMedical Research, Novartis Campus
Shantanu Karkare: Novartis Institutes for BioMedical Research, Novartis Campus
Marc Bergdoll: Institut de Biologie Moléculaire des Plantes, CNRS, Unité Propre de Recherche 2357
Alain Rahier: Institut de Biologie Moléculaire des Plantes, CNRS, Unité Propre de Recherche 2357
Juliet R. Leighton-Davis: Novartis Institutes for BioMedical Research, Novartis Campus
Celine Fioretto: Novartis Institutes for BioMedical Research, Novartis Campus
Thomas Aust: Novartis Institutes for BioMedical Research, Novartis Campus
Ireos Filipuzzi: Novartis Institutes for BioMedical Research, Novartis Campus
Mathias Frederiksen: Novartis Institutes for BioMedical Research, Novartis Campus
John Gounarides: Novartis Institutes for BioMedical Research
Dominic Hoepfner: Novartis Institutes for BioMedical Research, Novartis Campus
Andreas Hofmann: Novartis Institutes for BioMedical Research, Novartis Campus
Pierre-Eloi Imbert: Novartis Institutes for BioMedical Research, Novartis Campus
Rolf Jeker: Novartis Institutes for BioMedical Research, Novartis Campus
Richard Knochenmuss: Novartis Institutes for BioMedical Research, Novartis Campus
Philipp Krastel: Novartis Institutes for BioMedical Research, Novartis Campus
Anais Margerit: Novartis Institutes for BioMedical Research, Novartis Campus
Klaus Memmert: Novartis Institutes for BioMedical Research, Novartis Campus
Charlotte V. Miault: Novartis Institutes for BioMedical Research, Novartis Campus
N. Rao Movva: Novartis Institutes for BioMedical Research, Novartis Campus
Alban Muller: Novartis Institutes for BioMedical Research, Novartis Campus
Hans-Ulrich Naegeli: Novartis Institutes for BioMedical Research, Novartis Campus
Lukas Oberer: Novartis Institutes for BioMedical Research, Novartis Campus
Vivian Prindle: GNF
Ralph Riedl: Novartis Institutes for BioMedical Research, Novartis Campus
Sven Schuierer: Novartis Institutes for BioMedical Research, Novartis Campus
Jessica A. Sexton: Novartis Institutes for BioMedical Research
Jianshi Tao: GNF
Trixie Wagner: Novartis Institutes for BioMedical Research, Novartis Campus
Hong Yin: Novartis Institutes for BioMedical Research
Juan Zhang: Novartis Institutes for BioMedical Research, Novartis Campus
Silvio Roggo: Novartis Institutes for BioMedical Research, Novartis Campus
Stefan Reinker: Novartis Institutes for BioMedical Research, Novartis Campus
Christian N. Parker: Novartis Institutes for BioMedical Research, Novartis Campus

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9613

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