Hemiasterlin analogues incorporating an aromatic, and heterocyclic type C-terminus: design, synthesis and biological evaluation

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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Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.15.174 ◽

2019 ◽

Vol 15 ◽

pp. 1805-1814 ◽

Cited By ~ 2

Author(s):

Rosana Ribić ◽

Ranko Stojković ◽

Lidija Milković ◽

Mariastefania Antica ◽

Marko Cigler ◽

...

Keyword(s):

Muramyl Dipeptide ◽

Biological Evaluation ◽

Adjuvant Activity ◽

Design Synthesis ◽

C Terminus ◽

Minimal Structure ◽

Dipeptide Analogues ◽

Peptide Derivatives ◽

Mannose Receptors ◽

Synthesis And Biological Evaluation

Muramyl dipeptide is the minimal structure of peptidoglycan with adjuvant properties. Replacement of the N-acetylmuramyl moiety and increase of lipophilicity are important approaches in the preparation of muramyl dipeptide analogues with improved pharmacological properties. Mannose receptors present on immunocompetent cells are pattern-recognition receptors and by mannose ligands binding they affect the immune system. Here we present the design, synthesis and biological evaluation of novel mannosylated desmuramyl peptide derivatives. Mannose was coupled to dipeptides containing a lipophilic adamantane on N- or C-terminus through a glycolyl or hydroxyisobutyryl linker. Adjuvant activities of synthesized compounds were investigated in the mouse model using ovalbumin as an antigen. Their activities were compared to the previously described mannosylated adamantane-containing desmuramyl peptide and peptidoglycan monomer. Tested compounds exhibited adjuvant activity and the strongest enhancement of IgG production was stimulated by compound 21 (Man-OCH2-ᴅ-(1-Ad)Gly-ʟ-Ala-ᴅ-isoGln).

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Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides

10.3762/bxiv.2019.8.v1 ◽

2019 ◽

Author(s):

Rosana Ribić ◽

Ranko Stojković ◽

Lidija Milković ◽

Mariastefania Antica ◽

Marko Cigler ◽

...

Keyword(s):

Muramyl Dipeptide ◽

Biological Evaluation ◽

Adjuvant Activity ◽

Design Synthesis ◽

C Terminus ◽

Minimal Structure ◽

Dipeptide Analogues ◽

Peptide Derivatives ◽

Present Design ◽

Synthesis And Biological Evaluation

Muramyl dipeptide is the minimal structure of peptidoglycan with adjuvant properties. Replacement of the N-acetylmuramyl moiety and increase of lipophilicity are important approaches in the preparation of muramyl dipeptide analogues with improved pharmacological properties. Mannose receptors present on immunocompetent cells are pattern-recognition receptors and by mannose ligands binding they affect the immune system. Here we present design, synthesis and biological evaluation of novel mannosylated desmuramyl peptide derivatives. Mannose was coupled to dipeptide containing lipophilic adamantane on N- or C-terminus through glycolyl or hydroxyisobutyryl linker. Adjuvant activities of synthesized compounds were investigated in the mouse model using ovalbumin as an antigen. Their activities were compared to the previously described mannosylated adamantane-containing desmuramyl peptide and peptidoglycan monomer. Tested compounds exhibited adjuvant activity and the strongest enhancement of IgG production was stimulated by the compound 21 (Man-OCH2-D-(1-Ad)Gly-L-Ala-D-isoGln).

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