FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-10-12

AUTHORS

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, Christian N. Parker

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. More... »

PAGES

8613

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ncomms9613

DOI

http://dx.doi.org/10.1038/ncomms9613

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1038845926

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26456460


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