Karkare, Shantanu and Bergdoll, Marc and Leighton-Davies, Juliet and Filipuzzi, Ireos and Fioretto, Celine and Hoepfner, Dominic and Hofmann, Andreas and Imbert, Pierre-Eloi and Jeker, Rolf and Knochenmuss, Richard and Krastel, Philipp and Margerit, Anais and Memmert, Klaus and Miault, Charlotte and Movva, Rao and Naegeli, Hans Ulrich and Oberer, Lukas and Rahier, Alain and Reinker, Stefan and Riedl, Ralph and Roggo, Silvio and Sexton, Jessica and Schuierer, Sven and Wagner, Beatrix and Zhang, Juan and Helliwell, Stephen and Parker, Christian (2015) FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p. Nature Communications, 6. p. 8613. ISSN 2041-1723

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.

Item Type:	Article
Related URLs:	Author
Additional Information:	Poster for this publication has already been approved and published.
Keywords:	Erg26p cholesterol ergosterol
Related URLs:	Author
Date Deposited:	27 Oct 2015 00:45
Last Modified:	04 Jul 2016 23:46
URI:	https://oak.novartis.com/id/eprint/11382