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Title: Identification of a synthetic muramyl peptide derivative with enhanced Nod2 stimulatory capacity
Authors: Rubino, Stephen J
Magalhaes, Joao G.
Philpott, Dana
Bahr, George M. 
Blanot, Didier
Girardin , Stephen E
Affiliations: Faculty of Medicine 
Keywords: NOD2
Muramyl peptides
Muramyl dipeptide
Innate immunity
Subjects: Inflammation
Issue Date: 2013
Part of: Journal of innate immunity
Volume: 19
Issue: 5
Start page: 439
End page: 503
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 Crohns 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 Crohns disease.
DOI: 10.1177/1753425912471691
Open URL: Link to full text
Type: Journal Article
Appears in Collections:Faculty of Medicine

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