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

慢性炎症是癌症、心血管疾病和神经退行性变的标志，神经退行性变是由促炎症脂质介质，即前列腺素E2和白三烯推动的。非类固醇抗炎药(NSAIDs)抑制前列腺素的形成，但有严重的副作用。选择性抑制微粒体前列腺素E2合成酶(MPGES)-1，优先与抑制白三烯的形成相结合，被认为是一种安全的替代方案。我们最近发现维生素E的代谢物和各种半合成的类似物积聚在免疫细胞中，并通过靶向5-脂氧合酶来减轻炎症，似乎没有阻碍拆分，我们发现mPGES-1是另一个靶点。潜水项目的目的将是设计和表征有效和平衡的mPGES-1和5-脂氧合酶抑制剂，从内源性维生素E代谢物开始，既保持非类固醇抗炎药的预期活性，又避免它们的缺点。

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.