Perspective of microsomal prostaglandin E₂ synthase-1 as drug target in inflammation-related disorders

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• 作者：Andreas Koeberle¹ ; ^{andreas.koeberle@uni-jena.de" class="auth_mail" title="E-mail the corresponding author} ; Oliver Werz ; ^{oliver.werz@uni-jena.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Eicosanoid ; Micrososmal prostaglandin E2 synthase-1 ; NSAID ; Inflammation ; Lipid mediator
• 刊名：Biochemical Pharmacology
• 出版年：2015
• 出版时间：1 November 2015
• 年：2015
• 卷：98
• 期：1
• 页码：1-15
• 全文大小：2068 K

文摘

Prostaglandin (PG)E₂ encompasses crucial roles in pain, fever, inflammation and diseases with inflammatory component, such as cancer, but is also essential for gastric, renal, cardiovascular and immune homeostasis. Cyclooxygenases (COX) convert arachidonic acid to the intermediate PGH₂ which is isomerized to PGE₂ by at least three different PGE₂ synthases. Inhibitors of COX – non-steroidal anti-inflammatory drugs (NSAIDs) – are currently the only available therapeutics that target PGE₂ biosynthesis. Due to adverse effects of COX inhibitors on the cardiovascular system (COX-2-selective), stomach and kidney (COX-1/2-unselective), novel pharmacological strategies are in demand. The inducible microsomal PGE₂ synthase (mPGES)-1 is considered mainly responsible for the excessive PGE₂ synthesis during inflammation and was suggested as promising drug target for suppressing PGE₂ biosynthesis. However, 15 years after intensive research on the biology and pharmacology of mPGES-1, the therapeutic value of mPGES-1 as drug target is still vague and mPGES-1 inhibitors did not enter the market so far. This commentary will first shed light on the structure, mechanism and regulation of mPGES-1 and will then discuss its biological function and the consequence of its inhibition for the dynamic network of eicosanoids. Moreover, we (i) present current strategies for interfering with mPGES-1-mediated PGE₂ synthesis, (ii) summarize bioanalytical approaches for mPGES-1 drug discovery and (iii) describe preclinical test systems for the characterization of mPGES-1 inhibitors. The pharmacological potential of selective mPGES-1 inhibitor classes as well as dual mPGES-1/5-lipoxygenase inhibitors is reviewed and pitfalls in their development, including species discrepancies and loss of in vivo activity, are discussed.