| Texto completo | |
| Autor(es): Mostrar menos - |
Schwarz, Patrik F.
;
Perhal, Alexander F.
;
Guder, Famke
;
Gonzalez, Jorge Enrique Hernandez
;
Janssen, Kerrin
;
Sagiroglu, Ece
;
Tahir, Ammar
;
Kirchmair, Johannes
;
Rochel, Natacha
;
Dirsch, Verena M.
;
Chen, Ya
Número total de Autores: 11
|
| Tipo de documento: | Artigo Científico |
| Fonte: | Journal of Natural Products; v. 88, n. 8, p. 14-pg., 2025-07-28. |
| Resumo | |
Targeting retinoic acid-related orphan receptor gamma (ROR gamma) 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 (15), as a new inverse agonist of ROR gamma. The compound exhibited IC50 values of 0.4 mu M and 0.9 mu M in Gal4-ROR gamma and full-length ROR gamma luciferase assays, respectively. Compound 15 showed improved potency and efficacy compared to a structurally related known inverse agonist, betulinic acid. Among the four additional analogues tested (15.1-15.4), two (15.2 and 15.3) also demonstrated ROR gamma inverse agonist activity with low micromolar IC50 values in Gal4-ROR gamma luciferase assay. Real-time quantitative polymerase chain reaction experiments confirmed that compounds 15, 15.2, and 15.3 downregulated ROR gamma target genes. Thermal shift assays showed that both betulinic acid and 15 stabilized the ROR gamma ligand-binding domain. Molecular docking and structure-activity relationship analysis revealed distinct binding modes within the ROR gamma ligand-binding domains, further supported by site-directed mutagenesis. These findings expand the repertoire of ROR gamma inverse agonists based on the pentacyclic triterpenoid scaffolds. (AU) | |
| Processo FAPESP: | 24/13327-2 - Integração da Flexibilidade Proteica em Modelos de Aprendizado de Máquina para Identificação Virtual de Hits |
| Beneficiário: | Jorge Enrique Hernández González |
| Modalidade de apoio: | Bolsas no Brasil - Programa Fixação de Jovens Doutores |
| Processo FAPESP: | 22/03901-8 - Identificação de inibidores contra toxinas esfoliativas estafilocócicas por meio de técnicas computacionais |
| Beneficiário: | Jorge Enrique Hernández González |
| Modalidade de apoio: | Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado |