Shifting the Biosynthesis of Leukotrienes Toward Specialized Pro-Resolving Mediators by the 5-Lipoxygenase-Activating Protein (FLAP) Antagonist BRP-201

Christian Kretzer; Paul M Jordan; Rossella Bilancia; Antonietta Rossi; Tuğçe Gür Maz; Erden Banoglu; Ulrich S Schubert; Oliver Werz

doi:10.2147/JIR.S345510

Shifting the Biosynthesis of Leukotrienes Toward Specialized Pro-Resolving Mediators by the 5-Lipoxygenase-Activating Protein (FLAP) Antagonist BRP-201

J Inflamm Res. 2022 Feb 9:15:911-925. doi: 10.2147/JIR.S345510. eCollection 2022.

Authors

Christian Kretzer¹, Paul M Jordan¹, Rossella Bilancia², Antonietta Rossi², Tuğçe Gür Maz³, Erden Banoglu³, Ulrich S Schubert^{4

5}, Oliver Werz^{1

5}

Affiliations

¹ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, 07743, Germany.
² Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, I-80131, Italy.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06560, Ankara, Turkey.
⁴ Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Jena, 07743, Germany.
⁵ Jena Center for Soft Matter (JCSM) Friedrich Schiller University Jena, Jena, 07743, Germany.

Abstract

Background and purpose: Lipid mediators (LM) play crucial roles in the complex inflammation process with respect to initiation, maintenance, and resolution. Proinflammatory leukotrienes (LTs), generated by 5-lipoxygenase (LOX) and the 5-LOX-activating protein (FLAP), initiate and maintain inflammation while specialized pro-resolving mediators (SPMs) formed by various LOXs as key enzymes promote inflammation resolution and the return to homeostasis. Since 5-LOX also contributes to SPM biosynthesis, smart pharmacological manipulation of the 5-LOX pathway and accompanied activation of 12-/15-LOXs may accomplish suppression of LT formation but maintain or even elevate SPM formation. Here, we demonstrated that the FLAP antagonist BRP-201 possesses such pharmacological profile and causes a switch from LT toward SPM formation.

Methods and results: Comprehensive LM metabololipidomics with activated human monocyte-derived macrophages (MDM) of M1 or M2 phenotype showed that BRP-201 strongly inhibits LT formation induced by bacterial exotoxins. In parallel, SPM levels and 12/15-LOX-derived products were markedly elevated, in particular in M2-MDM. Intriguingly, in unstimulated MDM, BRP-201 induced formation of 12/15-LOX products including SPM and caused 15-LOX-1 subcellular redistribution without affecting 5-LOX. Experiments with HEK293 cells stably expressing either 5-LOX with or without FLAP, 15-LOX-1 or 15-LOX-2 confirmed suppression of 5-LOX product formation due to FLAP antagonism by BRP-201 but activated 15-LOX-1 in the absence of FLAP. Finally, in zymosan-induced murine peritonitis, BRP-201 (2 mg/kg, ip) lowered LT levels but elevated 12/15-LOX products including SPMs.

Conclusion: BRP-201 acts as FLAP antagonist but also as 12/15-LOX activator switching formation of pro-inflammatory LTs toward inflammation-resolving SPM, which reflects a beneficial pharmacological profile for intervention in inflammation.

Keywords: leukotrienes; lipid mediators; lipoxygenase; specialized pro-resolving mediators.

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG), Collaborative Research Center SFB 1278 “PolyTarget” (project number 316213987, projects A04 and Z01). The study of the chemical development of BRP-201 was supported by The Scientific and Technological Research Council of Turkey (TÜBİTAK Grant No: 112S596).