The nuclear receptor RAR-related orphan receptor gamma (RORγ) plays a pivotal role
in the differentiation of naïve CD4+T cells towards pro-inflammatory T helper 17 (Th17)
cells [1]. This distinct lineage of T helper cells are important host defenders but also contribute
to various autoimmune diseases like rheumatoid arthritis, multiple sclerosis, psoriasi
and severe neutrophilic asthma [2]
[3]. To improve treatment of these ailments, new innovative therapeutic approaches like
RORγ inverse agonists are heavily sought after.
In this study, we have identified a triterpenoid RORγ inverse agonist by luciferase
assays. This natural product demonstrated potent (IC50=119 nM) and selective inhibition of the RORγ nuclear receptor over other nuclear
receptors commonly modulated by triterpenes. To investigate the differences in binding
mode between this new inverse agonist and weak RORγ inverse agonists such as oleanolic
acid (IC50=9 µM) [4], we conducted molecular docking, which revealed distinct binding modes. These results
were further validated by using site-directed mutagenesis and luciferase assays. Furthermore,
we conducted biological examinations on both gene (qPCR) and protein levels (flow
cytometry): Upon treatment, we found a significant decrease in the expression of RORγ
target genes glucose-6-phosphatase [5] and interleukin-17 [1] and showed a reduction in Th17 differentiation, further corroborating the potential
of this unprecedented natural product.
In conclusion, we have successfully identified and characterised a new potent and
selective natural triterpenoid RORγ inverse agonist, which could serve as a useful
tool compound for future endeavours.
