Adamantane Containing Peptidoglycan Fragments Enhance RANTES and IL-6 Production in Lipopolysaccharide-Induced Macrophages

Manček-Keber, Mateja; Ribić, Rosana; Chain, Fernando Ezequiel; Sinnaeve, Davy; Martins, José; Jerala, Roman; Tomić, Srđanka; Fehér, Krisztina

doi:10.3390/molecules25163707

Cited by 6 publications

(6 citation statements)

References 30 publications

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“…Therefore, within this study, we have explored the modification of the D-Glu at the α-COOH group. In addition to better ligand binding to NOD2, the proposed design will also enable greater exposure of the adamantane structure for possible membrane anchoring, compared to those of ManAdDMP analogs [25,26].…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Desmuramyl Dipeptides Modified by Adamantyl-1,2,3-triazole

et al. 2021

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Muramyl dipeptide (MDP) is the smallest peptidoglycan fragment able to trigger the immune response. Structural modification of MDP can lead to the preparation of analogs with improved immunostimulant properties, including desmuramyl peptides (DMPs). The aim of this work was to prepare the desmuramyl peptide (L-Ala-D-Glu)-containing adamantyl-triazole moiety and its mannosylated derivative in order to study their immunomodulatory activities in vivo. The adjuvant activity of the prepared compounds was evaluated in a murine model using ovalbumin as an antigen, and compared to the reference adjuvant ManAdDMP. The results showed that the introduction of the lipophilic adamantyl-triazole moiety at the C-terminus of L-Ala-D-Glu contributes to the immunostimulant activity of DMP, and that mannosylation of DMP modified with adamantyl-triazole causes the amplification of its immunostimulant activity.

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Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Desmuramyl Dipeptides Modified by Adamantyl-1,2,3-triazole

et al. 2021

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“…By comparing the values, two observations may become relevant for the design of these molecules. Previously, we have shown 34 that the peptide co-stimulation activity to LPS on The Journal of Physical Chemistry B pubs.acs.org/JPCB Article macrophages was further increased by the incorporation of the compounds into phosphatidylcholine lipid bilayers. Only L-Ad 1 Tp and Man-L-Ad 1 Tp were investigated in the in vitro assay for this effect.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…We may also see a slight influence of the chirality of the adamantyl group attachment. Immune co-stimulation activities to LPS in vitro were also shown to be dependent on the chirality of the adamantyl group attachment, 34 but this is likely related to molecular details of the receptor interaction. Of the nonmannosylated diastereoisomer pair, D-Ad 1 Tp appears to interact weaker with the lipid bilayer than L-Ad 1 Tp.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…15 The best adjuvant activity was observed for the mannosylated derivate Man-D-Ad 1 Tp. 16 Adjuvant effects of the adamantylated PGN derivatives were also assessed in an in vitro assay 34 monitoring cytokine and chemokine production in immortalized mouse bone marrow-derived macrophages. We found that while the PGN compounds do not stimulate macrophages alone, L-Ad 1 Tp and, in particular, Man-L-Ad 1 Tp were able to enhance the immune responses induced by lipopolysaccharide (LPS) on macrophages.…”

Section: ■ Introductionmentioning

confidence: 99%

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Targeted Delivery of Adamantylated Peptidoglycan Immunomodulators in Lipid Nanocarriers: NMR Shows That Cargo Fragments Are Available on the Surface

et al. 2020

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We present an in-depth investigation of the membrane interactions of peptidoglycan (PGN)-based immune adjuvants designed for lipid-based delivery systems using NMR spectroscopy. The derivatives contain a cargo peptidoglycan (PGN) dipeptide fragment and an adamantyl group, which serves as an anchor to the lipid bilayer. Furthermore, derivatives with a mannose group that can actively target cell surface receptors on immune cells are also studied. We showed that the targeting mannose group and the cargo PGN fragment are both available on the lipid bilayer surface, thereby enabling interactions with cognate receptors. We found that the nonmannosylated compounds are incorporated stronger into the lipid assemblies than the mannosylated ones, but the latter compounds penetrate deeper in the bilayer. This might be explained by stronger electrostatic interactions available for zwitterionic nonmannosylated derivatives as opposed to the compounds in which the charged N-terminus is capped by mannose groups. The higher incorporation efficiency of the nonmannosylated compounds correlated with a larger relative enhancement in immune stimulation activities upon lipid incorporation compared to that of the derivatives with the mannose group. The chirality of the adamantyl group also influenced the incorporation efficiency, which in turn correlated with membrane-associated conformations that affect possible intermolecular interactions with lipid molecules. These findings will help in improving the development of PGN-based immune adjuvants suitable for delivery in lipid nanoparticles.

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“…Our research is focused on the preparation of MDP mimetics, primarily modified by lipophilic adamantane due to the fact that adamantane DMPs are devoid of the undesirable side-effect [ 6 ]. Additionally, bulky adamantane can act as a membrane anchor and can be used for the preparation of liposomes and other similar drug delivery systems [ 24 , 25 , 26 , 27 ]. First, we prepared DMPs in which adamantyl moieties replaced the muramic acid of MDP [ 22 ] and then they were further modified by mannosylation [ 10 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Immunological Evaluation of Mannosylated Desmuramyl Dipeptides Modified by Lipophilic Triazole Substituents

Peroković

Car

Bušljeta

et al. 2022

IJMS

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Muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine, MDP) is the smallest peptidoglycan fragment able to trigger an immune response by activating the NOD2 receptor. Structural modification of MDP can lead to analogues with improved immunostimulating properties. The aim of this work was to prepare mannosylated desmuramyl peptides (ManDMP) containing lipophilic triazole substituents to study their immunomodulating activities in vivo. The adjuvant activity of the prepared compounds was evaluated in the mouse model using ovalbumin as an antigen and compared to the MDP and referent adjuvant ManDMPTAd. The obtained results confirm that the α-position of D-isoGln is the best position for the attachment of lipophilic substituents, especially adamantylethyl triazole. Compound 6c exhibited the strongest adjuvant activity, comparable to the MDP and better than referent ManDMPTAd.

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Adamantane Containing Peptidoglycan Fragments Enhance RANTES and IL-6 Production in Lipopolysaccharide-Induced Macrophages

Cited by 6 publications

References 30 publications

Design, Synthesis, and Biological Evaluation of Desmuramyl Dipeptides Modified by Adamantyl-1,2,3-triazole

Design, Synthesis, and Biological Evaluation of Desmuramyl Dipeptides Modified by Adamantyl-1,2,3-triazole

Targeted Delivery of Adamantylated Peptidoglycan Immunomodulators in Lipid Nanocarriers: NMR Shows That Cargo Fragments Are Available on the Surface

Synthesis and Immunological Evaluation of Mannosylated Desmuramyl Dipeptides Modified by Lipophilic Triazole Substituents

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