1. Distinctive Immune Signatures Driven by Structural Alterations in Desmuramylpeptide NOD2 Agonists
- Author
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Janež, Špela, Guzelj, Samo, Kocbek, Petra, de Vlieger, Eveline A., Slütter, Bram, and Jakopin, Žiga
- Abstract
Herein we report on the design, synthesis and biological evaluation of a series of nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) desmuramylpeptide agonists. The structural prerequisites that shape both physicochemical and immunomodulatory profiles of desmuramylpeptide NOD2 agonists have been delineated. Within this context, we identified 3, a butyrylated desmuramylpeptide, as a potent in vitroNOD2 agonist (EC50= 4.6 nM), exhibiting an almost 17-fold enhancement in potency compared to its unsubstituted counterpart 1(EC50= 77.0 nM). The novel set of desmuramylpeptides demonstrate unique in vitroimmunomodulatory activities. They elicited cytokine production in peripheral blood mononuclear cells (PBMCs), both alone and in conjunction with lipopolysaccharide (LPS). The spermine-decorated 32also stimulated the LPS-induced cytotoxic activity (2.95-fold) of PBMCs against K562 cancer cells. Notably, the cholesterol-conjugate 26displayed anti-inflammatory actions, highlighted by its capacity to convert the inflammatory monocyte subset into an anti-inflammatory phenotype. Finally, the eicosapentaenoylated derivative 23augmented antigen presentation by mouse bone marrow-derived dendritic cells (BMDCs), thus highlighting its potential as a vaccine adjuvant.
- Published
- 2024
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