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

作者：Ribeiro Alison; Pontis Silvia; Mengatto Luisa; Armirotti Andrea; Chiurchiu Valerio; Capurro Valeria; Fiasella Annalisa; Nuzzi Andrea; Romeo Elisa; Moreno Sanz Guillermo; Maccarrone Mauro; Reggiani Angelo; Tarzia Giorgio; Mor Marco; Bertozzi Fabio; Bandiera Tiziano; Piomelli Daniele^*

来源：ACS Chemical Biology, 2015, 10(8): 1838-1846.

DOI：10.1021/acschembio.5b00114

Fatty acid ethanolamides such as palmitoylethanolamide (PEA) and oteoylethanolamide (OEA) are lipid-derived mediators that potently inhibit pain and inflammation by ligating type-alpha peroxisome proliferator-activated receptors (PPAR-alpha). 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 beta-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's 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.

• 出版日期2015-8