Abstract
Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (27a), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E2 synthase-1. Compound 27a is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead.
Highlights
Deficiency of vitamin E causes a dysfunctional immune response, degenerative diseases, and potentially atherosclerosis and Alzheimer’s disease.1−5 The discovery that the vital antioxidant vitamin E mediates immune functions through endogenous long-chain metabolites (LCMs) recently revived research on this field.6−8 long-chain metabolites of vitamin E (LCMs) are produced from αtocopherol (1a) and other vitamin E forms (1b−d, 6a−d) by hepatic ω-oxidation, yielding ω-alcohols and ωcarboxylic acids, which are excreted via bile and feces, shortened by successive β-oxidations, or conjugated with sulfate or glucoronate for urinary elimination.7,8 The LCMs αT-13′-CH2OH (9a) and α-T-13′-COOH (12a) were detected at low nanomolar concentrations in human plasma, albeit with strong variation between individuals.6,8,9 These differences in1a metabolism may provide an explanation for the mixed outcomes of human vitamin E intervention studies8,10,11 and open the door toward personalized pharmacotherapy
While substituents at C5 and C7 of chromanol provide limited options to improve 5-LOX inhibition, all of these modifications substantially impaired the suppression of 5-LOX product biosynthesis in PMNL (Tables 1 and 2, Schemes S1 and S2), and we conclude that the natural chromanol moiety of vitamin E already represents an evolutionally optimized compromise between potent 5-LOX inhibition and access to the enzyme in innate immune cells
As a reason for this gain in 5-LOX inhibitory activity, we found that 27a strongly accumulates in PMNL (Figure 3B), as previously described for the endogenous vitamin E metabolite 12a, which is enriched in immune cells, both in vitro and in the inflamed peritoneal cavity in vivo.6 5
Summary
Deficiency of vitamin E causes a dysfunctional immune response, degenerative diseases, and potentially atherosclerosis and Alzheimer’s disease.− The discovery that the vital antioxidant vitamin E mediates immune functions through endogenous long-chain metabolites (LCMs) recently revived research on this field.− LCMs are produced from αtocopherol (1a) and other vitamin E forms (1b−d, 6a−d) by hepatic ω-oxidation, yielding ω-alcohols and ωcarboxylic acids, which are excreted via bile and feces, shortened by successive β-oxidations, or conjugated with sulfate or glucoronate for urinary elimination. The LCMs αT-13′-CH2OH (9a) and α-T-13′-COOH (12a) were detected at low nanomolar concentrations in human plasma, albeit with strong variation between individuals. These differences in. While substituents at C5 and C7 of chromanol provide limited options to improve 5-LOX inhibition, all of these modifications substantially impaired the suppression of 5-LOX product biosynthesis in PMNL (Tables 1 and 2, Schemes S1 and S2), and we conclude that the natural chromanol moiety of vitamin E already represents an evolutionally optimized compromise between potent 5-LOX inhibition and access to the enzyme in innate immune cells. Compound 27a potently suppressed the biosynthesis of LTB4 and other 5-LOX products (i.e., 5-hydroxyeicosatetraenoic acid (5-HETE), LTB4 isomers) in PMNL (A23187 plus arachidonic acid: IC50 = 0.04 μM; A23187: IC50 = 0.05 μM) (Figure 3A), with superior potency as compared to the cell-free assay (Table 2). Compound 27a is orally available and distributed to the lung, thereby effectively suppressing pulmonary LT levels and asthmatic airway contraction
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