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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Helliwell SB,Karkare S,Bergdoll M,Rahier A,Leighton-Davis JR,Fioretto C,Aust T,Filipuzzi I,Frederiksen M,Gounarides J,Hoepfner D,Hofmann A,Imbert PE,Jeker R,Knochenmuss R,Krastel P,Margerit A,Memmert K,Miault CV,Raodoi
10.1038/ncomms9613subject
Has Abstractpub_date
2015-10-12 00:00:00pages
8613issn
2041-1723pii
ncomms9613journal_volume
6pub_type
杂志文章abstract：:Ferroelectric materials exhibit a phase transition to a paraelectric state driven by temperature - called the Curie transition. In conventional ferroelectrics, the Curie transition is caused by a change in crystal symmetry, while the material itself remains a continuous three-dimensional solid crystal. However, ferroe...
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pub_type： 杂志文章,评审
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更新日期：2020-10-06 00:00:00
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更新日期：2019-01-11 00:00:00
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更新日期：2019-06-17 00:00:00
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更新日期：2014-10-21 00:00:00
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