Project is founded by Croatian Science Foundation (Hrvatska zaklada za znanost) under the number IP-2025-02-5568

Duration: 10.06.2025.-09.12.2028.

Total cost: 195.950,00 EUR

ABSTRACT: Muramyl-dipeptide (MDP) represents the minimal peptidoglycan fragment exhibiting adjuvant activity. The human immune system recognizes MDP as a pathogen-associated molecular pattern (PAMP), triggering an immune response through activation of the NOD2 receptor. Enhancing the pharmacological properties of MDP is achieved by increasing its lipophilicity and synthesizing desmuramyl-peptide (DMP) derivatives. Furthermore, the adjuvant potency of DMP can be augmented by conjugation with mannose (Man), enabling specific recognition by mannose receptors expressed on immunocompetent cells. This study proposes the synthesis of novel aromatic, organometallic, and mannose-conjugated DMP derivatives, which will undergo comprehensive structural characterization and biological evaluation. The key research objectives include: (i) assessing the immunomodulatory effects of rationally designed aromatic, organometallic, and mannosylated peptide adjuvant derivatives in both in vitro and in vivo models, (ii) investigating the activation of NOD2 and mannose receptors through experimental and computational approaches, and (iii) exploring the potential of lipophilic Man-DMP conjugates for developing immunologically active lipid-based formulations. Lipid formulations offer an additional means of modulating immune responses while facilitating targeted delivery. The findings of this research will contribute to a deeper understanding of the structure-activity relationship of peptide-based adjuvants, elucidating their immune activation mechanisms and their potential application in lipid-based immunotherapeutic formulations.