Institute of Human Virology, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
Institute of Human Virology, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
Bioorg Chem. 2019 Sep;90:103077. doi: 10.1016/j.bioorg.2019.103077. Epub 2019 Jun 21.
Retinoid-related orphan receptor gamma-t (RORγt) belongs to the nuclear receptor superfamily that takes vital roles in the development and maturation of T-helper 17 cell (Th17) and lymph-node genesis. Because Th17 cells have been proved to be major effectors in human autoimmune and inflammatory diseases, the agonists and antagonists of RORγt have been discovered as promising leads for the therapeutics of these diseases. Most of the current studies of RORγt inhibitors have been focused on ligand binding domain (LBD) of RORγt because the structure and binding pockets of LBD have been elucidated and studied in detail. Recent research elucidated that the hinge domain (HD) of RORγt was significantly involved in the SUMOylation of RORγt and thus specifically affecting T cell development but not lymph-node genesis. These discoveries highlighted the potential of HD of RORγt as the target of RORγt inhibitors that could specifically inhibit Th17-related activities without affecting lymph-node genesis. In this study, we utilized a screening system with full-length RORγt including DBD, HD and LBD to evaluate the activities of a synthesized library of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives. We identified a potent lead compound (28) that effectively inhibited Th17 cell differentiation. Docking and structure-activity relationship (SAR) studies showed that compound 28 may not bind in the binding pocket as most of the known inhibitors, but may bind in the pocket closed to Gln223 and Leu244 in HD. Our studies showed evidence that the HD of RORγt could afford a binding pocket for Th17 specific inhibitors and this domain should be further studied to discover potent and specific RORγt inhibitors.
视黄酸相关孤儿受体γ- t（RORγt）属于核受体超家族，在辅助性 T 细胞 17（Th17）细胞的发育和成熟以及淋巴结生成中起着重要作用。因为已经证明 Th17 细胞是人类自身免疫和炎症性疾病的主要效应物，所以 RORγt 的激动剂和拮抗剂已被发现为这些疾病治疗的有前途的先导化合物。目前对 RORγt 抑制剂的研究大多集中在 RORγt 的配体结合域（LBD）上，因为 LBD 的结构和结合口袋已经被阐明并进行了详细研究。最近的研究表明，RORγt 的铰链域（HD）显著参与了 RORγt 的 SUMOylation，从而特异性地影响 T 细胞的发育，但不影响淋巴结的生成。这些发现突出了 RORγt 的 HD 作为 RORγt 抑制剂的靶点的潜力，该靶点可以特异性地抑制与 Th17 相关的活性，而不影响淋巴结的生成。在这项研究中，我们利用包含 DBD、HD 和 LBD 的全长 RORγt 的筛选系统来评估合成的四氢苯并[4,5]噻吩并[2,3-d]嘧啶衍生物文库的活性。我们鉴定了一种有效的潜在先导化合物（28），可有效抑制 Th17 细胞分化。对接和构效关系（SAR）研究表明，化合物 28 可能不会像大多数已知的抑制剂那样结合在结合口袋中，而是可能结合在 HD 中靠近 Gln223 和 Leu244 的口袋中。我们的研究表明，RORγt 的 HD 可以提供一个与 Th17 特异性抑制剂结合的口袋，应该进一步研究该结构域，以发现有效的、特异性的 RORγt 抑制剂。
