Ye Bai-Xin, Deng Xu, Shao Li-Dong, Lu Ying, Xiao Run, Liu Yi-Jie, Jin Yi, Xie Yin-Yin, Zhao Yan, Luo Liu-Fei, Ma Shun, Gao Ming, Zhang Lian-Ru, He Juan, Zhang Wei-Na, Chen Yi, Xia Cheng-Feng, Deng Min, Liu Ting-Xi, Zhao Qin-Shi, Chen Sai-Juan, Chen Zhu
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China;
J Immunol. 2015 May 1;194(9):4489-97. doi: 10.4049/jimmunol.1402798. Epub 2015 Mar 25.
Interstitial leukocyte migration plays a critical role in inflammation and offers a therapeutic target for treating inflammation-associated diseases such as multiple sclerosis. Identifying small molecules to inhibit undesired leukocyte migration provides promise for the treatment of these disorders. In this study, we identified vibsanin B, a novel macrocyclic diterpenoid isolated from Viburnum odoratissimum Ker-Gawl, that inhibited zebrafish interstitial leukocyte migration using a transgenic zebrafish line (TG:zlyz-enhanced GFP). We found that vibsanin B preferentially binds to heat shock protein (HSP)90β. At the molecular level, inactivation of HSP90 can mimic vibsanin B's effect of inhibiting interstitial leukocyte migration. Furthermore, we demonstrated that vibsanin B ameliorates experimental autoimmune encephalomyelitis in mice with pathological manifestation of decreased leukocyte infiltration into their CNS. In summary, vibsanin B is a novel lead compound that preferentially targets HSP90β and inhibits interstitial leukocyte migration, offering a promising drug lead for treating inflammation-associated diseases.
间质白细胞迁移在炎症中起关键作用，并为治疗诸如多发性硬化症等炎症相关疾病提供了一个治疗靶点。鉴定抑制不必要白细胞迁移的小分子为治疗这些疾病带来了希望。在本研究中，我们鉴定出了紫珠素B，一种从珊瑚树中分离出的新型大环二萜类化合物，它使用转基因斑马鱼品系（TG:zlyz-增强型绿色荧光蛋白）抑制斑马鱼间质白细胞迁移。我们发现紫珠素B优先结合热休克蛋白（HSP）90β。在分子水平上，HSP90失活可模拟紫珠素B抑制间质白细胞迁移的作用。此外，我们证明紫珠素B可改善小鼠实验性自身免疫性脑脊髓炎，其病理表现为白细胞向中枢神经系统浸润减少。总之，紫珠素B是一种新型先导化合物，它优先靶向HSP90β并抑制间质白细胞迁移，为治疗炎症相关疾病提供了一个有前景的药物先导。
