氮杂莫卢京，一种莫卢京衍生物，对髓样分化因子88（MyD88）和TIR结构域衔接蛋白诱导干扰素β（TRIF）依赖性信号通路具有抑制活性。
Azamollugin, a mollugin derivative, has inhibitory activity on MyD88- and TRIF-dependent pathways.
作者信息
Nakajima Yuki, Nishino Hitomi, Takahashi Kazunori, Nugroho Alfarius Eko, Hirasawa Yusuke, Kaneda Toshio, Morita Hiroshi
机构信息
School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41 Shinagawa-Ku, Tokyo, 142-8501, Japan.
出版信息
J Nat Med. 2025 Jan;79(1):36-44. doi: 10.1007/s11418-024-01842-x. Epub 2024 Sep 16.
Previously, we reported that azamollugin, an aza-derivative of mollugin, exhibited potent inhibitory activity on NO production in LPS-stimulated RAW 264.7 cells. Further investigations in this study revealed that azamollugin not only suppressed iNOS gene expression regulated by NF-κB, but also inhibited LPS-induced IFN-β expression, which is known to be regulated by IRF3. Azamollugin exhibited an inhibitory activity on LPS-induced IRAK1 activation, suggesting inhibitory effect on the MyD88-dependent pathway. Furthermore, azamollugin inhibited LPS-induced phosphorylation of IRF3 and its upstream factor, TBK1/IKKε, suggesting an inhibitory effect on the TRIF-dependent pathway via TLR4. In addition, azamollugin also suppressed poly(I:C)-induced phosphorylation of TBK1 and IRF3, suggesting an inhibitory effect on the TRIF-dependent pathway via TLR3. These results suggest that azamollugin has inhibitory activity against both the MyD88-dependent and TRIF-dependent pathways, respectively.
此前，我们报道过氮杂摩卢亭，一种摩卢亭的氮杂衍生物，对脂多糖（LPS）刺激的RAW 264.7细胞中一氧化氮（NO）的产生具有强大的抑制活性。本研究的进一步调查显示，氮杂摩卢亭不仅抑制由核因子κB（NF-κB）调控的诱导型一氧化氮合酶（iNOS）基因表达，还抑制LPS诱导的干扰素-β（IFN-β）表达，已知该表达受干扰素调节因子3（IRF3）调控。氮杂摩卢亭对LPS诱导的白细胞介素-1受体相关激酶1（IRAK1）激活表现出抑制活性，表明对髓样分化因子88（MyD88）依赖途径有抑制作用。此外，氮杂摩卢亭抑制LPS诱导的IRF3及其上游因子TANK结合激酶1（TBK1）/IKKε激酶（IKKε）的磷酸化，表明对通过Toll样受体4（TLR4）的TIR结构域衔接蛋白诱导干扰素β（TRIF）依赖途径有抑制作用。另外，氮杂摩卢亭还抑制多聚肌苷酸-多聚胞苷酸（poly(I:C)）诱导的TBK1和IRF3的磷酸化，表明对通过Toll样受体3（TLR3）的TRIF依赖途径有抑制作用。这些结果表明，氮杂摩卢亭分别对MyD88依赖途径和TRIF依赖途径具有抑制活性。
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