Karkare, Shantanu, Bergdoll, Marc, Leighton-Davies, Juliet, Filipuzzi, Ireos, Fioretto, Celine, Hoepfner, Dominic, Hofmann, Andreas, Imbert, Pierre-Eloi, Jeker, Rolf, Knochenmuss, Richard, Krastel, Philipp, Margerit, Anais, Memmert, Klaus, Miault, Charlotte, Movva, Rao, Naegeli, Hans Ulrich, Oberer, Lukas, Rahier, Alain, Reinker, Stefan, Riedl, Ralph, Roggo, Silvio, Sexton, Jessica, Schuierer, Sven, Wagner, Beatrix, Zhang, Juan, 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