BRP-187: A potent inhibitor of leukotriene biosynthesis that acts through impeding the dynamic 5-lipoxygenase/5-lipoxygenase-activating protein (FLAP) complex assembly

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• 作者：Ulrike Garscha^a ; ¹ ; ^{ulrike.garscha@uni-jena.de" class="auth_mail" title="E-mail the corresponding author} ; Susanna Voelker^a ; ¹ ; ^{susanna.voelker@gmx.de" class="auth_mail" title="E-mail the corresponding author} ; Simona Pace^a ; ^{simona.pace@uni-jena.de" class="auth_mail" title="E-mail the corresponding author} ; Jana Gerstmeier^a ; ^{jana.gerstmeier@uni-jena.de" class="auth_mail" title="E-mail the corresponding author} ; Besa Emini^a ; ^{eminibesa@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Stefanie Liening^a ; ^{stefanie.liening@uni-jena.de" class="auth_mail" title="E-mail the corresponding author} ; Antonietta Rossi^b ; ^{antrossi@unina.it" class="auth_mail" title="E-mail the corresponding author} ; Christina Weinigel^c ; ^{christina.weinigel@med.uni-jena.de" class="auth_mail" title="E-mail the corresponding author} ; Silke Rummler^c ; ^{silke.rummler@med.uni-jena.de" class="auth_mail" title="E-mail the corresponding author} ; Ulrich S. Schubert^d ; ^e ; ^{ulrich.schubert@uni-jena.de" class="auth_mail" title="E-mail the corresponding author} ; Gerhard K.E. Scriba^a ; ^{gerhard.scriba@uni-jena.de" class="auth_mail" title="E-mail the corresponding author} ; Erşan Ç ; elikoğlu^f ; ^{ersancelikoglu@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Burcu Ç ; alışkan^f ; ^{brcaliskan@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Erden Banoglu^f ; ^{banoglu@gazi.edu.tr" class="auth_mail" title="E-mail the corresponding author} ; Lidia Sautebin^b ; ^{sautebin@unina.it" class="auth_mail" title="E-mail the corresponding author} ; Oliver Werz^a ; ^d ; ^{oliver.werz@uni-jena.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：5-LO ; 5-lipoxygenase ; AA ; arachidonic acid ; COX ; cyclooxygenase ; cPLA2 ; cytosolic phospholipase A2 ; FLAP ; 5-lipoxygenase-activating protein ; fMLP ; N-formyl-methionyl-leucyl-phenylalanine ; H(P)ETE ; hydro(pero)oxyeicosatetraenoic acid ; HHT ; hydroxyheptadecatrienoic acid ; IL ; interleukin ; LPS ; lipopolysaccharide ; LT ; leukotriene ; mPGES-1 ; microsomal prostaglandin E2 synthase 1 ; MPO ; myeloperoxidase ; PG ; phosphate-buffered saline plus 1  ; mg/ml glucose ; PGC ; phosphate-buffered saline plus 1 
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：119
• 期：Complete
• 页码：17-26
• 全文大小：721 K

文摘

The pro-inflammatory leukotrienes (LTs) are formed from arachidonic acid (AA) in activated leukocytes, where 5-lipoxygenase (5-LO) translocates to the nuclear envelope to assemble a functional complex with the integral nuclear membrane protein 5-LO-activating protein (FLAP). FLAP, a MAPEG family member, facilitates AA transfer to 5-LO for efficient conversion, and LT biosynthesis critically depends on FLAP. Here we show that the novel LT biosynthesis inhibitor BRP-187 prevents the 5-LO/FLAP interaction at the nuclear envelope of human leukocytes without blocking 5-LO nuclear redistribution. BRP-187 inhibited 5-LO product formation in human monocytes and polymorphonuclear leukocytes stimulated by lipopolysaccharide plus N-formyl-methionyl-leucyl-phenylalanine (IC₅₀ = 7–10 nM), and upon activation by ionophore A23187 (IC₅₀ = 10–60 nM). Excess of exogenous AA markedly impaired the potency of BRP-187. Direct 5-LO inhibition in cell-free assays was evident only at >35-fold higher concentrations, which was reversible and not improved under reducing conditions. BRP-187 prevented A23187-induced 5-LO/FLAP complex assembly in leukocytes but failed to block 5-LO nuclear translocation, features that were shared with the FLAP inhibitor MK886. Whereas AA release, cyclooxygenases and related LOs were unaffected, BRP-187 also potently inhibited microsomal prostaglandin E₂ synthase-1 (IC₅₀ = 0.2 μM), another MAPEG member. In vivo, BRP-187 (10 mg/kg) exhibited significant effectiveness in zymosan-induced murine peritonitis, suppressing LT levels in peritoneal exudates as well as vascular permeability and neutrophil infiltration. Together, BRP-187 potently inhibits LT biosynthesis in vitro and in vivo, which seemingly is caused by preventing the 5-LO/FLAP complex assembly and warrants further preclinical evaluation.