Dual Inhibitors inspired from Vitamin E: towards vitamin E analogs that relieve inflammation by targeting mPGES-1 and 5-lipoxygenase without impeding resolution

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Chronic inflammation is a hallmark of cancer, cardiovascular disease and neurodegeneration that is driven by pro-inflammatory lipid mediators, i.e. prostaglandin E2 and leukotrienes. Non-steroidal anti-inflammatory drugs (NSAIDs) suppress prostaglandin formation but are afflicted with severe side effects. Selective inhibition of microsomal prostaglandin E2 synthase (mPGES)-1, preferentially in combination with suppression of leukotriene formation, is considered as a safe alternative. We recently found that vitamin E metabolites along with various semisynthetic analogues accumulate in immune cells and relieve inflammation by targeting 5-lipoxygenase, seemingly without impeding resolution, and we revealed mPGES-1 as additional target. The aim of the DIVE project will be to design and characterize potent and balanced inhibitors of mPGES-1 and 5-lipoxygenase starting from endogenous vitamin E metabolites that retain the desired activity of NSAIDs while avoiding their drawbacks.