Muramyl peptides activate innate immunity conjointly via YB1 and NOD2.

Bacterial cell wall muramyl dipeptide (MDP) and glucosaminyl-MDP (GMDP) are potent activators of innate immunity. Two receptor targets, NOD2 and YB1, have been reported; we investigated potential overlap of NOD2 and YB1 pathways. Separate knockdown of NOD2 and YB1 demonstrates that both contribute to GMDP induction of NF-κB expression, a marker of innate immunity, although excess YB1 led to induction in the absence of NOD2.

GMDP: unusual physico-chemical and biological properties of the anomeriс forms.

Disaccharide containing unit of peptidoglycan from bacterial cell wall, N-acetyl-d-glucosaminyl-N-acetylmuramyl-l-alanyl-d-glutaminamide (gluсosaminyl-muramyl-dipeptide) registered in Russia as an immunomodulatory drug, is shown to participate in slow equilibrium of α and β anomeric forms. Data of NMR spectra and molecular dynamics indicate that the α-anomer predominantly acquires a folded conformation stabilized by intramolecular hydrogen bond between the alanyl carbonyl and muramyl NH proton. The β-form displays a considerable fraction of extended, non-hydrogen bonded structures.

Evidence for correlation between the intensities of adjuvant effects and NOD2 activation by monomeric, dimeric and lipophylic derivatives of N-acetylglucosaminyl-N-acetylmuramyl peptides.

Adjuvanticity of a series of peptidoglycan fragments-known as muramyl peptides-and their lipophylic derivatives was examined and compared with the ability of these compounds to activate NF-kB pathway through NOD2. The adjuvant activity of di, tetrasaccharide peptides and stearoyl containing derivatives has at least two peaks in dose-response curves and the greater of them correlates with respective dose-response data for NF-kB stimulation through NOD2. Introduction of stearoyl moiety, with the aim of improving muramyl peptide interaction with the cell membrane and subsequent intracellular delivery, influenced the corresponding activities in vitro, but did not correlate with improved effects in vivo experiments.