The identification of naturally occurring neoruscogenin as a bioavailable, potent, and high-affinity agonist of the nuclear receptor RORα (NR1F1)

Plants represent a tremendous structural diversity of natural compounds that bind to many different human disease targets and are potentially useful as starting points for medicinal chemistry programs. This resource is, however, still underexploited due to technical difficulties with the identificat...

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Bibliographic Details
Published in:	Journal of biomolecular screening Vol. 19; no. 3; p. 399
Main Authors:	Helleboid, Stéphane, Haug, Christian, Lamottke, Kai, Zhou, Yijun, Wei, Jianbing, Daix, Sébastien, Cambula, Linda, Rigou, Géraldine, Hum, Dean W, Walczak, Robert
Format:	Journal Article
Language:	English
Published:	United States 01-03-2014
Subjects:	Biological Products - pharmacology Drug Discovery High-Throughput Screening Assays Nuclear Receptor Subfamily 1, Group F, Member 1 - agonists Plant Extracts - chemistry Plant Extracts - pharmacology Reproducibility of Results Small Molecule Libraries Spirostans - pharmacology natural products NR1F1 RORα neoruscogenin plant extracts high-throughput screening
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Summary:	Plants represent a tremendous structural diversity of natural compounds that bind to many different human disease targets and are potentially useful as starting points for medicinal chemistry programs. This resource is, however, still underexploited due to technical difficulties with the identification of minute quantities of active ingredients in complex mixtures of structurally diverse compounds upon raw phytomass extraction. In this work, we describe the successful identification of a novel class of potent RAR-related orphan receptor alpha (RORα or nuclear receptor NR1F1) agonists from a library of 12,000 plant extract fractions by using an optimized, robust high-throughput cell-free screening method, as well as an innovative hit compound identification procedure through further extract deconvolution and subsequent structural elucidation of the active natural compound(s). In particular, we demonstrate that neoruscogenin, a member of the steroidal sapogenin family, is a potent and high-affinity RORα agonist, as shown by its activity in RORα reporter assays and from its effect on RORα target gene expression in vitro and in vivo. Neoruscogenin represents a universal pharmacological tool for RORα research due to its specific selectivity profile versus other nuclear receptors, its excellent microsomal stability, good bioavailability, and significant peripheral exposure in mouse.
ISSN:	1552-454X
DOI:	10.1177/1087057113497095