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.