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Abstract：
Chronic inflammation results from excessive pro-inflammatory signaling and the failure to resolve the inflammatory reaction. Lipid mediators orchestrate both the initiation and resolution of inflammation. Switching from pro-inflammatory to pro-resolving lipid mediator biosynthesis is considered as efficient strategy to relieve chronic inflammation, though drug candidates exhibiting such features are unknown. Starting from a library of Vietnamese medical plant extracts, we identified isomers of the biflavanoid 8-methylsocotrin-4\'-ol from Dracaena cambodiana, which limit inflammation by targeting 5-lipoxygenase and switching the lipid mediator profile from leukotrienes to specialized pro-resolving mediators (SPM). Elucidation of the absolute configurations of 8-methylsocotrin-4\'-ol revealed the 2S,γS-isomer being most active, and molecular docking studies suggest that the compound binds to an allosteric site between the 5-lipoxygenase subdomains. We identified additional subordinate targets within lipid mediator biosynthesis, including microsomal prostaglandin E2 synthase-1. Leukotriene production is efficiently suppressed in activated human neutrophils, macrophages, and blood, while the induction of SPM biosynthesis is restricted to M2 macrophages. The shift from leukotrienes to SPM was also evident in mouse peritonitis in vivo and accompanied by a substantial decrease in immune cell infiltration. In summary, we disclose a promising drug candidate that combines potent 5-lipoxygenase inhibition with the favorable reprogramming of lipid mediator profiles.
摘要：
慢性炎症是由过度的促炎信号和不能解决炎症反应引起的。脂质介质协调炎症的开始和解决。从促炎转向促解脂质介质生物合成被认为是缓解慢性炎症的有效策略。尽管具有这种特征的候选药物是未知的。从越南药用植物提取物图书馆开始，我们鉴定了来自龙血树的双黄酮8-甲基socotrin-4'-ol的异构体，通过靶向5-脂氧合酶并将脂质介质谱从白三烯转换为专门的促分解介质（SPM）来限制炎症。8-甲基socotrin-4'-ol的绝对构型的阐明揭示了2S，γS-异构体最活跃，和分子对接研究表明，该化合物与5-脂氧合酶亚结构域之间的变构位点结合。我们确定了脂质介体生物合成中的其他从属靶标，包括微粒体前列腺素E2合酶-1。白三烯的产生在激活的人中性粒细胞中被有效抑制，巨噬细胞，和血，而SPM生物合成的诱导仅限于M2巨噬细胞。从白三烯到SPM的转变在体内小鼠腹膜炎中也很明显，并伴随着免疫细胞浸润的显着减少。总之,我们公开了一种有前景的候选药物，它结合了有效的5-脂氧合酶抑制和脂质介质谱的有利重编程。
