Abstract
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.
Highlights
Biological roles of RORs and their potential as drug targets Biological roles of RORs Consequences of ROR agonism and RORs as drug targets Natural ligands directly binding to RORs Steroids Cholesterol and cholesterol sulfate Cholesterol biosynthetic intermediates Oxysterols Secosteroids Neoruscogenin Terpenoids Ursolic acid Betulinaldehyde Ganoderone A Methyl corosolate, uvaol and oleanolic acid Rockogenin Retinoids Amethinol A Polyketides Iso avones Nobiletin Cardiac glycosides Digoxin and derivatives Preclinical studies performed with digoxin Digoxin as RORg(t)-agonist? Natural products indirectly affecting RORs
It is likely that intermediates and metabolites of the cholesterol metabolism act as endogenous ligands for RORs.[1,2,3]
Calculations revealed that a further increase in occupancy would require very high concentration of ligands, which might explain the moderate effect of exogenous ligands in reporter assays containing serum.[1]
Summary
The retinoic acid receptor-related orphan receptors (ROR) a, b, and g are a subfamily of nuclear receptors, encoded by the RORA-C (or NR1F1-3) genes. If the His–Tyr lock is broken, the aromatic interactions are terminated and helix 12 is destabilized as a consequence.[8,9,10] Inverse agonistic ligands are Angela Ladurner studied Molecular Biology at the University of Vienna (Austria) and completed her doctoral studies on natural product research in the group of Verena Dirsch in 2013. She worked as a postdoctoral scientist at the Medical University of Vienna and at the University of Vienna. This is apparent by the fact that between 1981 and 2014, approximately 50% of newly approved drugs are inspired by natural products, be it natural products, natural product analogues, or synthetic mimetics.[23]
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