Samo Guzelj (Author), Sanja Vrbek (Author), Martina Gobec (Author), Stane Pajk (Author), Veronika Klančič (Author), Bram Slütter (Author), Ruža Frkanec (Author), Adela Štimac (Author), Primož Šket (Author), Janez Plavec (Author), Irena Mlinarič-Raščan (Author), Žiga Jakopin (Author)

Abstract

We report on the design, synthesis, and biological evaluation of a series of nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) desmuramylpeptide agonists with improved in vitro and in vivo adjuvant properties. We identified two promising compounds: 68, a potent nanomolar in vitro NOD2 agonist, and the more lipophilic 75, which shows superior adjuvant activity in vivo. Both compounds had immunostimulatory effects on peripheral blood mononuclear cells at the protein and transcriptional levels, and augmented dendritic-cell-mediated activation of T cells, while 75 additionally enhanced the cytotoxic activity of peripheral blood mononuclear cells against malignant cells. The C18 lipophilic tail of 75 is identified as a pivotal structural element that confers in vivo adjuvant activity in conjunction with a liposomal delivery system. Accordingly, liposome-encapsulated 75 showed promising adjuvant activity in mice, surpassing that of muramyl dipeptide, while achieving a more balanced Th1/Th2 immune response, thus highlighting its potential as a vaccine adjuvant.

Keywords

reakcijski produkti;reaction products;peptides and proteins;cells;organic compounds;toxicity;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.4:54
COBISS: 64930051 Link will open in a new window
ISSN: 0022-2623
Views: 88
Downloads: 66
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Other data

Secondary language: Slovenian
Secondary keywords: Farmacevtska kemija;Peptidi;Toksičnost;Organske spojine;
Type (COBISS): Article
Pages: str. 7809-7838
Volume: ǂVol. ǂ64
Issue: ǂiss. ǂ11
Chronology: 2021
DOI: 10.1021/acs.jmedchem.1c00644
ID: 16608079