title: A Potent Systemically Active N-Acylethanolamine Acid Amidase Inhibitor that Suppresses Inflammation and Human Macrophage Activation.
abstract: Fatty acid ethanolamides such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are lipid-derived mediators that potently inhibit pain and inflammation by ligating type-α peroxisome proliferator-activated receptors (PPAR-α). 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 β-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.
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Alison
authors: A
authors: Ribeiro
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Silvia
authors: S
authors: Pontis
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Luisa
authors: L
authors: Mengatto
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Andrea
authors: A
authors: Armirotti
authors: ‡European Center for Brain Research, Fondazione Santa Lucia, via del Fosso di Fiorano 64/65, 00143 Rome, Italy.
authors: Valerio
authors: V
authors: Chiurchiù
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Valeria
authors: V
authors: Capurro
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Annalisa
authors: A
authors: Fiasella
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Andrea
authors: A
authors: Nuzzi
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Elisa
authors: E
authors: Romeo
authors: §Department of Anatomy and Neurobiology, University of California, Irvine, California 92697-4625, United States.
authors: Guillermo
authors: G
authors: Moreno-Sanz
authors: §Department of Anatomy and Neurobiology, University of California, Irvine, California 92697-4625, United States.|∥Campus Bio-Medico University of Rome, via Alvaro del Portillo 21, 00128, Rome, Italy.
authors: Mauro
authors: M
authors: Maccarrone
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Angelo
authors: A
authors: Reggiani
authors: ⊥Department of Biomolecular Science, University of Urbino "Carlo Bo", 61029 Urbino, Italy.
authors: Giorgio
authors: G
authors: Tarzia
authors: #Pharmaceutical Department, University of Parma, I-43100 Parma, Italy.
authors: Marco
authors: M
authors: Mor
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Fabio
authors: F
authors: Bertozzi
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors: Tiziano
authors: T
authors: Bandiera
authors: †Drug Discovery and Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.|∇Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, California 92697, United States.
authors: Daniele
authors: D
authors: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D047090:beta-Lactams / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D047090:beta-Lactams; D000581:Amidohydrolases; C523108:NAAA protein, human