Wang Yonghui, Cai Wei, Tang Ting, Liu Qian, Yang Ting, Yang Liuqing, Ma Yingli, Zhang Guifeng, Huang Yafei, Song Xiaoxia, Orband-Miller Lisa A, Wu Qianqian, Zhou Ling, Xiang Zhijun, Xiang Jia-Ning, Leung Stewart, Shao Liming, Lin Xichen, Lobera Mercedes, Ren Feng
School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai 201203, China.
Research and Development, GlaxoSmithKline, No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, China.
ACS Med Chem Lett. 2018 Jan 22;9(2):120-124. doi: 10.1021/acsmedchemlett.7b00476. eCollection 2018 Feb 8.
Biaryl amides as new RORγt modulators were discovered. The crystal structure of biaryl amide agonist in complex with RORγt ligand binding domain (LBD) was resolved, and both "short" and "long" inverse agonists were obtained by removing from or adding to a proper structural moiety. While "short" inverse agonist () recruits a corepressor peptide and dispels a coactivator peptide, "long" inverse agonist () dispels both. The two types of inverse agonists can be utilized as potential tools to study mechanisms of Th17 transcriptional network inhibition and related disease biology.
发现了作为新型RORγt调节剂的联芳基酰胺。解析了联芳基酰胺激动剂与RORγt配体结合域（LBD）复合物的晶体结构，并通过从适当结构部分去除或添加来获得“短”和“长”反向激动剂。“短”反向激动剂（）募集共抑制肽并驱散共激活肽，而“长”反向激动剂（）则驱散两者。这两种类型的反向激动剂可作为研究Th17转录网络抑制机制和相关疾病生物学的潜在工具。
