Špela Bizjak (Author), Samo Guzelj (Author), Petra Kocbek (Author), Eveline A. de Vlieger (Author), Bram Slütter (Author), Žiga Jakopin (Author)

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 vitro NOD2 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 vitro immunomodulatory activities. They elicited cytokine production in peripheral blood mononuclear cells (PBMCs), both alone and in conjunction with lipopolysaccharide (LPS). The spermine-decorated 32 also stimulated the LPS-induced cytotoxic activity (2.95-fold) of PBMCs against K562 cancer cells. Notably, the cholesterol-conjugate 26 displayed anti-inflammatory actions, highlighted by its capacity to convert the inflammatory monocyte subset into an anti-inflammatory phenotype. Finally, the eicosapentaenoylated derivative 23 augmented antigen presentation by mouse bone marrow-derived dendritic cells (BMDCs), thus highlighting its potential as a vaccine adjuvant.

Keywords

agonists;cells;peptides and proteins;reaction products;toxicity;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.9+615.375
COBISS: 209432835 Link will open in a new window
ISSN: 1520-4804
Views: 29
Downloads: 4
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Other data

Secondary language: Slovenian
Secondary keywords: agonisti;celice;peptidi in proteini;reakcijski produkti;Toksičnost;Imunomodulatorji;
Type (COBISS): Article
Pages: <v tisku>
Volume: ǂVol. ǂ
Issue: ǂno. ǂ
Chronology: 2024
DOI: 10.1021/acs.jmedchem.4c01577
ID: 25266702