Abstract
We report the enhancement of the lipopolysaccharide-induced immune response by adamantane containing peptidoglycan fragments in vitro. The immune stimulation was detected by Il-6 (interleukine 6) and RANTES (regulated on activation, normal T cell expressed and secreted) chemokine expression using cell assays on immortalized mouse bone-marrow derived macrophages. The most active compound was a α-D-mannosyl derivative of an adamantylated tripeptide with L-chirality at the adamantyl group attachment, whereby the mannose moiety assumed to target mannose receptors expressed on macrophage cell surfaces. The immune co-stimulatory effect was also influenced by the configuration of the adamantyl center, revealing the importance of specific molecular recognition event taking place with its receptor. The immunostimulating activities of these compounds were further enhanced upon their incorporation into lipid bilayers, which is likely related to the presence of the adamantyl group that helps anchor the peptidoglycan fragment into lipid nanoparticles. We concluded that the proposed adamantane containing peptidoglycan fragments act as co-stimulatory agents and are also suitable for the preparation of lipid nanoparticle-based delivery of peptidoglycan fragments.
Highlights
Muramyl dipeptide (MDP), N-acetylmuramyl-L-alanyl-D-isoglutamine, is the minimal essentialThe innate immune is based recognition ofactivity dangerby signals, such as the of microbial structural unit of PGN system responsible for on its the immunological the stimulationNOD2 components of pathogens.This is enabled by families of pattern recognition receptors (PRRs) expressed receptors [3]
When the cells were subsequently challenged with LPS, Man-l-adamantylated tripeptide (AdTp) strongly increased LPS induced Il6 (* p < 0.05, Figure 2a) and Rantes (* p < 0.05, Figure 2c) mRNA production
In the case of the non-mannosylated derivatives, a significant (* p < 0.05) Il6 and Rantes increase was detected for l-AdTp
Summary
The innate immune is based recognition ofactivity dangerby signals, such as the of microbial structural unit of PGN system responsible for on its the immunological the stimulation. This is enabled by families of pattern recognition receptors (PRRs) expressed receptors [3]. Structure–activity studies of the MDP derivatives and analogues suggest that L-Ala-Dby macrophages and other recognize peptidoglycan (PGN), is a major isoGln pharmacophore is immune essentialcells for [1]. PRRs lipophilic substituents into MDP analogues have been shown to increase its adjuvant activity [4,5,6] are classified.
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