Discovery of betulinaldehyde as a natural RORγt agonist

Feng Yang; Ruihan Zhang; Dongxuan Ni; Xiaomin Luo; Shijie Chen; Cheng Luo; Weilie Xiao

doi:10.1016/j.fitote.2019.104200

Discovery of betulinaldehyde as a natural RORγt agonist

Fitoterapia. 2019 Sep:137:104200. doi: 10.1016/j.fitote.2019.104200. Epub 2019 Jun 10.

Authors

Feng Yang¹, Ruihan Zhang², Dongxuan Ni², Xiaomin Luo³, Shijie Chen⁴, Cheng Luo⁵, Weilie Xiao⁶

Affiliations

¹ School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai 201203, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chongzhi Road, Shanghai 201203, China.
² Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, 2 Rd. Cuihubei, 650091 Kunming, China.
³ Drug Discovery and Design Center, State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chongzhi Road, Shanghai 201203, China.
⁴ Drug Discovery and Design Center, State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chongzhi Road, Shanghai 201203, China. Electronic address: shijiechen@simm.ac.cn.
⁵ School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai 201203, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chongzhi Road, Shanghai 201203, China; Department of Pharmacy, Fujian Medical University, Fuzhou 350001, China; Department of Pharmacy, Guiyang University of Traditional Chinese Medicine, South Dong Qing Road, Guizhou 550025, China. Electronic address: cluo@simm.ac.cn.
⁶ Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, 2 Rd. Cuihubei, 650091 Kunming, China. Electronic address: xiaoweilie@ynu.edu.cn.

PMID: 31195082
DOI: 10.1016/j.fitote.2019.104200

Abstract

Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a dual-functional therapeutic target. The agonists and inhibitors of RORγt are potential agents for tumor immunotherapy and autoimmune diseases, respectively, and sometimes share similar scaffolds. Although the widely distributed triterpenoid ursolic acid (UA) has been identified as a RORγt inhibitor, the report of a triterpenoid RORγt agonist is still absent. By screening an in-house triterpenoid library, we uncovered a novel RORγt agonist, betulinaldehyde (1), together with an inhibitor (2, 3β, 28-Dihydroxy-lupan-29-oic acid). Compound 1 showed a good RORγt activating effect with the EC₅₀ of 11.4 μM in Alpha Screen assay, and altered the thermal stability of RORγt by directly binding to the protein in vitro. Combined with the SPR assay, the Kd value of compound 1 was examined as 2.99 μM. The modulation mechanism of triterpenoid agonists and inhibitors were discussed by molecular docking. Herein, we firstly discovered compound 1 as a triterpenoid agonist of RORγt. The co-distribution of triterpenoid RORγt agonist and inhibitors in the same plant, might be related to the anti-inflammatory and anti-cancerous bioactivity of the plant extract.

Keywords: Alpha screen; Molecular docking; RORγt; Receptor agonist; Triterpenoids.

MeSH terms

Aldehydes / pharmacology*
Humans
Molecular Docking Simulation
Molecular Structure
Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
Phytochemicals / pharmacology
Triterpenes / pharmacology*

Substances

Aldehydes
Nuclear Receptor Subfamily 1, Group F, Member 3
Phytochemicals
RORC protein, human
Triterpenes