FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p
AuthorHelliwell, SB; Karkare, S; Bergdoll, M; Rahier, A; Leighton-Davis, JR; Fioretto, C; Aust, T; Filipuzzi, I; Frederiksen, M; Gounarides, J; ...
Source TitleNature Communications
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sHOFMANN, ANDREAS
Document TypeJournal Article
CitationsHelliwell, S. B., Karkare, S., Bergdoll, M., Rahier, A., Leighton-Davis, J. R., Fioretto, C., Aust, T., Filipuzzi, I., Frederiksen, M., Gounarides, J., Hoepfner, D., Hofmann, A., Imbert, P. -E., Jeker, R., Knochenmuss, R., Krastel, P., Margerit, A., Memmert, K., Miault, C. V. ,... Parker, C. N. (2015). FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p. NATURE COMMUNICATIONS, 6 (1), https://doi.org/10.1038/ncomms9613.
Access StatusOpen Access
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.
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