A Potent Systemically Active N-Acylethanolamine Acid Amidase Inhibitor that Suppresses Inflammation and Human Macrophage Activation

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• 作者：Alison Ribeiro ; Silvia Pontis ; Luisa Mengatto ; Andrea Armirotti ; Valerio Chiurchi霉 ; Valeria Capurro ; Annalisa Fiasella ; Andrea Nuzzi ; Elisa Romeo ; Guillermo Moreno-Sanz ; Mauro Maccarrone ; Angelo Reggiani ; Giorgio Tarzia ; Marco Mor ; Fabio Bertozzi ; Tiziano Bandiera ; Daniele Piomelli
• 刊名：ACS Chemical Biology
• 出版年：2015
• 出版时间：August 21, 2015
• 年：2015
• 卷：10
• 期：8
• 页码：1838-1846
• 全文大小：475K
• ISSN：1554-8937

文摘

Fatty acid ethanolamides such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are lipid-derived mediators that potently inhibit pain and inflammation by ligating type-伪 peroxisome proliferator-activated receptors (PPAR-伪). These bioactive substances are preferentially degraded by the cysteine hydrolase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages. Here, we describe a new class of 尾-lactam derivatives that are potent, selective, and systemically active inhibitors of intracellular NAAA activity. The prototype of this class deactivates NAAA by covalently binding the enzyme鈥檚 catalytic cysteine and exerts profound anti-inflammatory effects in both mouse models and human macrophages. This agent may be used to probe the functions of NAAA in health and disease and as a starting point to discover better anti-inflammatory drugs.