Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides

Ribić, Rosana; Stojković, Ranko; Milković, Lidija; Antica, Mariastefania; Cigler, Marko; Tomić, Srđanka

doi:10.3762/bjoc.15.174

Cited by 16 publications

(24 citation statements)

References 51 publications

(63 reference statements)

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“…We have prepared DMPs containing lipophilic adamantane moieties attached at the Nand C-termini of L-Ala or D-isoGln, as well as their mannosylated derivatives. The results indicate that mannosylation of DMPs contributes to the stimulation of the immune response [10,11], possibly by affecting the immune response via the mannose receptor family [12,13]. The immunomodulatory activities of all prepared DMPs and their mannosylated derivatives were estimated in vivo, in murine models, based on the secondary humoral response to ovalbumin as a test antigen.…”

Section: Introductionmentioning

confidence: 98%

“…We have prepared DMPs containing lipophilic adamantane moieties attached at the N-and C-termini of L-Ala or D-isoGln, as well as their mannosylated derivatives. The results indicate that mannosylation of DMPs contributes to the stimulation of the immune response [10,11], possibly by Structure-activity studies of muropeptides have been performed in order to prepare an adjuvant with improved properties of the MDP molecule, and lipophilic analogs and derivatives of MDP have shown improved immunostimulant activity [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…The immunomodulatory activities of all prepared DMPs and their mannosylated derivatives were estimated in vivo, in murine models, based on the secondary humoral response to ovalbumin as a test antigen. In structure-activity relationship (SAR) studies, we have shown that glycoconjugates that contain a glycolyl linker between mannose and the DMP moiety exhibit a stronger adjuvant activity than analogs containing a hydroxyisobutyryl linker [11]. The most active adjuvant in this class of compounds is ManAdDMP (Figure 1), which has adamantane in the form of adamantylglycine between mannose and L-Ala. We have confirmed that MDP and ManAdDMP with a free carboxyl group at the side chain of the isoGln form strong interactions with the NOD2 receptor.…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…The binding affinity of β‐CD towards adamantane‐based compounds can be enhanced by attaching neutral, “solubilizing” functionalities (e.g., sugar subunits) . Such glycoconjugates (mannosides) were reported to be efficient immunostimulators and potential vaccine adjuvants . This class of compounds was also incorporated into liposomes, which exhibited promising carrier properties .…”

Section: Introductionmentioning

confidence: 99%

Solvophobically Driven Complexation of Adamantyl Mannoside with β‐Cyclodextrin in Water and Structured Organic Solvents

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Hanževački

Brkljača

et al. 2020

Chemistry A European J

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The effects of solventa nd temperature on the complexation of adamantyl mannoside with b-cyclodextrin and 6-O-monotosyl-6-deoxy-b-cyclodextrinw ere explored experimentally and by means of molecular dynamics simulations. Efficientb inding was observedo nly in hydrogenbondeds olvents, which indicated solvophobically driven complexation. Thes tability of the inclusion complex was considerably higheri na queous media. Ap ronouncedt emperature dependence of D r H * and D r S * ,r esulting in perfect enthalpy-entropy compensation, was observedi nw ater.The complexation thermodynamicsw as in line with classical rationale for the hydrophobic effect at lower temperatures and the nonclassical explanation at higher temperatures. This finding linked cyclodextrinc omplexation thermodynam-ics with insights regarding the effecto ft emperature on the hydration water structure. The complexation enthalpies and entropies were weakly dependent on temperature in organic media. The signs of D r H * and D r S * were in accordance with the nonclassicalh ydrophobic (solvophobic) effect.T he structures of the optimized product corresponded to those deduceds pectroscopically,a nd the calculated and experimentally obtained values of D r G * were in very good agreement. This investigation clearly demonstrated that solvophobically drivenf ormation of cyclodextrin complexes could be anticipated in structured solvents in general. However,u nlike in water, adamantane and the host cavity behaved solely as structure breakers in the organic media explored so far.[a] SE = standard error of the mean (N = 3o r4). Figure 6. Relative a) conformation and b) solvation contribution to the hydration enthalpies of reactantsand the complex over the studied temperature range.

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“…The best adjuvant activity in NIH/OlaHsd (H-2q) mice showed the mannosylated derivate Man-d-AdTp [19]. Its good adjuvant activity was also confirmed in BALBc mice [22]. Differences noticed in vivo and in vitro regarding the stereocentre at the adamantyl group may arise because of the experimental model.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2020

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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.

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Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides

Cited by 16 publications

References 51 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

Solvophobically Driven Complexation of Adamantyl Mannoside with β‐Cyclodextrin in Water and Structured Organic Solvents

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

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