20.500.12556/RUL-141424 Structural fine-tuning of desmuramylpeptide NOD2 agonists defines their in vivo adjuvant activity 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 C$_{18}$ 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. reaction products peptides proteins cells organic compounds toxicity reakcijski produkti farmacevtska kemija peptidi toksičnost organske spojine true false true Angleški jezik Slovenski jezik Članek v reviji 2022-09-29 08:24:54 2022-09-29 08:24:55 2023-03-02 03:39:29 0000-00-00 00:00:00 2021 0 0 Str. 7809-7838 iss. 11 Vol. 64 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 0022-2623 10.1021/acs.jmedchem.1c00644 64930051 RAZ_Guzelj_Samo_2021.pdf RAZ_Guzelj_Samo_2021.pdf 1 C761D8055516517510B13C20225695BB de9f65ca5caec051e2eef25e827d50af74e91f867a98fb3a69bf84b205841dfe fed46c5c-b836-11ed-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=166965 https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00644 1 6d4232bc-3fbf-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=162476 Fakulteta za farmacijo 0 0 0