Identification of the Natural Steroid Sapogenin Diosgenin as a Direct Dual-Specific RORα/γ Inverse Agonist.

The steroid sapogenin diosgenin is a well-known natural product with a plethora of described pharmacological activities including the amelioration of T helper 17 (Th17)-driven pathologies. However, the exact underlying mode of action of diosgenin leading to a dampened Th17 response is still largely unknown and specific molecular targets have yet to be identified. Here, we show that diosgenin acts as a direct ligand and inverse agonist of the nuclear receptor retinoic acid receptor (RAR)-related orphan receptor (ROR)α and RORγ, which are key transcription factors involved in Th17 cell differentiation and metabolism. IC50 values determined by luciferase reporter gene assays, employing constructs for either RORγ-Gal4 fusion proteins or full length receptors, were in the low micromolar range at around 2 µM. To highlight the functional consequences of this RORα/γ inverse agonism, we determined gene expression levels of important ROR target genes, i.e., IL-17A and glucose-6-phosphatase, in relevant cellular in vitro models of Jurkat T and HepG2 cells, respectively, by RT-qPCR (reverse transcription quantitative PCR). Thereby, it was shown that diosgenin leads to a dose-dependent decrease in target gene expressions consistent with its potent cellular ROR inverse agonistic activity. Additionally, in silico dockings of diosgenin to the ROR ligand-binding domain were performed to determine the underlying binding mode. Taken together, our results establish diosgenin as a novel, direct and dual-selective RORα/γ inverse agonist. This finding establishes a direct molecular target for diosgenin for the first time, which can further explain reported amendments in Th17-driven diseases by this compound.

Natural products as modulators of retinoic acid receptor-related orphan receptors (RORs).

Covering: 1994 to 2020 Retinoic acid receptor-related orphan receptors (RORs) belong to a subfamily of the nuclear receptor superfamily and possess prominent roles in circadian rhythm, metabolism, inflammation, and cancer. They have been subject of research for over two decades and represent attractive but challenging drug targets. Natural products were among the first identified ligands of RORs and continue to be of interest to this day. This review focuses on ligands and indirect modulators of RORs from natural sources and explores their roles in a therapeutic context.