1. Exploration of Long-Chain Vitamin e Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation
- Author
-
Andreas Koeberle, Denis Séraphin, Stefan Lorkowski, Tiago Rodrigues, Oliver Werz, Daniela Schuster, Dimitri Bréard, Hermann Stuppner, Ida Cerqua, Antonietta Rossi, Simona Pace, Marta C. Marques, Alexander S. Mosig, Paul M. Jordan, Stephan Permann, Jana Gerstmeier, Martin Raasch, Gonçalo J. L. Bernardes, André Gollowitzer, Ulrike Garscha, Chau-Phi Dinh, Alexia Ville, Jean-Jacques Helesbeux, Fiorentina Roviezzo, Guillaume Viault, Elena Brunner, Pascal Richomme, Veronika Temml, Rossella Bilancia, Khaled Alsabil, Konstantin Loeser, Konstantin Neukirch, Neukirch, K., Alsabil, K., Dinh, C. -P., Bilancia, R., Raasch, M., Ville, A., Cerqua, I., Viault, G., Breard, D., Pace, S., Temml, V., Brunner, E., Jordan, P. M., Marques, M. C., Loeser, K., Gollowitzer, A., Permann, S., Gerstmeier, J., Lorkowski, S., Stuppner, H., Garscha, U., Rodrigues, T., Bernardes, G. J. L., Schuster, D., Seraphin, D., Richomme, P., Rossi, A., Mosig, A. S., Roviezzo, F., Werz, O., Helesbeux, J. -J., Koeberle, A., Neukirch, Konstantin [0000-0003-0630-1624], Dinh, Chau-Phi [0000-0002-3683-3472], Gollowitzer, André [0000-0003-1524-8298], Stuppner, Hermann [0000-0001-8862-0201], Rodrigues, Tiago [0000-0002-1581-5654], Bernardes, Gonçalo J L [0000-0001-6594-8917], Schuster, Daniela [0000-0002-9933-8938], Séraphin, Denis [0000-0002-0509-5788], Mosig, Alexander S [0000-0002-5687-2444], Werz, Oliver [0000-0002-5064-4379], Koeberle, Andreas [0000-0001-6269-5088], Apollo - University of Cambridge Repository, and Bernardes, Gonçalo JL [0000-0001-6594-8917]
- Subjects
medicine.medical_treatment ,Administration, Oral ,Inflammation ,Endogeny ,Lipoxygenase Inhibitor ,Pharmacology ,Article ,chemistry.chemical_compound ,Structure-Activity Relationship ,Immune system ,Drug Discovery ,medicine ,Humans ,Vitamin E ,Lipoxygenase Inhibitors ,Prostaglandin E2 ,Leukotriene ,Arachidonate 5-Lipoxygenase ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Lipid signaling ,Recombinant Protein ,Recombinant Proteins ,Molecular Docking Simulation ,Molecular Medicine ,medicine.symptom ,Resolvin ,medicine.drug ,Human - 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.
- Published
- 2021