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Article Abstract
Targeting retinoic acid-related orphan receptor γ (RORγ) with inverse agonists presents a promising therapeutic strategy for treating autoimmune diseases, including psoriasis, rheumatoid arthritis, and multiple sclerosis. Through structure-based virtual screening, we identified a lupane-type pentacyclic triterpenoid, (2Z)-2-(2-furanylmethylene)-3-oxolup-20(29)-en-28-oic acid (), as a new inverse agonist of RORγ. The compound exhibited IC values of 0.4 μM and 0.9 μM in Gal4-RORγ and full-length RORγ luciferase assays, respectively. Compound showed improved potency and efficacy compared to a structurally related known inverse agonist, betulinic acid. Among the four additional analogues tested (-), two ( and ) also demonstrated RORγ inverse agonist activity with low micromolar IC values in Gal4-RORγ luciferase assay. Real-time quantitative polymerase chain reaction experiments confirmed that compounds , , and downregulated RORγ target genes. Thermal shift assays showed that both betulinic acid and stabilized the RORγ ligand-binding domain. Molecular docking and structure-activity relationship analysis revealed distinct binding modes within the RORγ ligand-binding domains, further supported by site-directed mutagenesis. These findings expand the repertoire of RORγ inverse agonists based on the pentacyclic triterpenoid scaffolds.
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| http://dx.doi.org/10.1021/acs.jnatprod.5c00416 | DOI Listing |
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