title: Identification of a synthetic muramyl peptide derivative with enhanced Nod2 stimulatory capacity.
abstract: Muramyl peptides (MPs) represent the building blocks of bacterial peptidoglycan, a critical component of bacterial cell walls. MPs are well characterized for their immunomodulatory properties, and numerous studies have delineated the role of MPs or synthetic MP analogs in host defense, adjuvanticity and inflammation. More recently, Nod1 and Nod2 have been identified as the host sensors for specific MPs, and, in particular, Nod2 was shown to detect muramyl dipeptide (MDP), a MP found in both Gram-positive and Gram-negative bacterial cell walls. Because mutations in Nod2 are associated with the etiology of Crohn's disease, there is a need to identify synthetic MP analogs that could potentiate Nod2-dependent immunity. Here, we analyzed the Nod2-activating property of 36 MP analogs that had been tested previously for their adjuvanticity and anti-infectious activity. Using a luciferase-based screen, we demonstrate that addition of a methyl group to the second amino acid of MDP generates a MDP derivative with enhanced Nod2-activating capacity. We further validated these results in murine macrophages, human dendritic cells and in vivo. These results offer a basis for the rational development of synthetic MPs that could be used in the treatment of inflammatory disorders that have been associated with Nod2 dysfunction, such as Crohn's disease.
authors: 1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors: Stephen J
authors: SJ
authors: Rubino
authors: Joao G
authors: JG
authors: Magalhaes
authors: Dana
authors: D
authors: Philpott
authors: George M
authors: GM
authors: Bahr
authors: Didier
authors: D
authors: Blanot
authors: Stephen E
authors: SE
authors: Girardin
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000276:immunology*; D000818:Animals; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008264:Macrophages / Q000276:immunology*; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011110:Polymorphism, Genetic; D015202:Protein Engineering; D015398:Signal Transduction / Q000235:genetics; D019076:Transgenes / Q000235:genetics
chemical_list: D015850:Interleukin-6; D053473:Nod2 Signaling Adaptor Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine
keywords: Nod2; adjuvant; inflammation; innate immunity; muramyl dipeptide; muramyl peptides