Leukotriene biosynthetic enzymes as therapeutic targets

Abstract

Leukotrienes are powerful immune-regulating lipid mediators with established pathogenic roles in inflammatory allergic diseases of the respiratory tract - in particular, asthma and hay fever. More recent work indicates that these lipids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, and metabolic diseases as well as cancer. Biosynthesis of leukotrienes involves oxidative metabolism of arachidonic acid and proceeds via a set of soluble and membrane enzymes that are primarily expressed by cells of myeloid origin. In activated immune cells, these enzymes assemble at the endoplasmic and perinuclear membrane, constituting a biosynthetic complex. This Review describes recent advances in our understanding of the components of the leukotriene-synthesizing enzyme machinery, emerging opportunities for pharmacological intervention, and the development of new medicines exploiting both antiinflammatory and pro-resolving mechanisms.

Novel highly potent OXE receptor antagonists with prolonged plasma lifetimes that are converted to active metabolites in vivo in monkeys

“…Arachidonic acid metabolites formed by the 5-lipoxygenase pathway are important mediators in asthma, and drugs targeting their biosynthesis reduce disease symptoms in humans (Haeggstrom, 2018;Peters-Golden & Henderson, 2007). While the focus has principally been on LTD 4 , acting through the selective CysLT 1 receptor (Peters-Golden & Henderson, 2007;Yokomizo, Nakamura, & Shimizu, 2018), other 5-LO products may also play a role.…”

Activation of metabolite receptor GPR91 promotes platelet aggregation and transcellular biosynthesis of leukotriene C4

“…Eicosanoids are a series of oxygenated metabolites of arachidonic acid (AA) with potent actions in hemostasis and inflammatory responses . Biosynthesis of eicosanoids begins with the release of free AA from membrane phospholipids catalyzed by cytosolic phospholipase A 2 (cPLA 2 ).…”

“…5,6 Eicosanoids are a series of oxygenated metabolites of arachidonic acid (AA) with potent actions in hemostasis and inflammatory responses. 7,8 Biosynthesis of eicosanoids begins with the release of free AA from membrane phospholipids catalyzed by cytosolic phospholipase A 2 (cPLA 2 ). Further metabolism of AA is mainly directed by two types of oxygenases, cyclooxygenases (COX-1 and COX-2) and lipoxygenases (5-, 12-, and 15-LOX), leading to the generation of prostaglandins, thromboxanes, hydroxy and dihydroxy fatty acids, including the leukotrienes, via enzymes in downstream pathways.…”

Phenolic acid phenethylesters and their corresponding ketones: Inhibition of 5‐lipoxygenase and stability in human blood and HepaRG cells

“…5‐LO and leukotrienes are intimately involved in the progression of inflammatory diseases like asthma, atherosclerosis and rheumatoid arthritis . Several key proteins associated with LT biosynthesis and action, including 5‐LO, have been investigated and validated as antiinflammatory targets . To date, zileuton ( 1 ) (Zyflo ® ) (Figure ) is the only drug which targets the leukotriene pathway through the inhibition of 5‐LO and is clinically approved in the United States for the chronic treatment of asthma .…”

“…[12][13][14][15] Several key proteins associated with LT biosynthesis and action, including 5-LO, have been investigated and validated as antiinflammatory targets. 16 To date, zileuton (1) (Zyflo ® ) (Figure 1) is the only drug which targets the leukotriene pathway through the inhibition of 5-LO and is clinically approved in the United States for the chronic treatment of asthma. 17 However, its use is limited due to hepatic side effects and an unfavorable pharmacokinetic profile.…”