Structural fine-tuning of desmuramylpeptide NOD2 agonists defines their in vivo adjuvant activity

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

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.

• Jezik: Angleški jezik
• Ključne besede: reaction products, peptides, proteins, cells, organic compounds, toxicity
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2021
• Št. strani: Str. 7809-7838
• Številčenje: Vol. 64, iss. 11
• PID: 20.500.12556/RUL-141424
• UDK: 615.4:54
• ISSN pri članku: 0022-2623
• DOI: 10.1021/acs.jmedchem.1c00644
• COBISS.SI-ID: 64930051
• Datum objave v RUL: 29.09.2022

Gradivo je del revije

• Naslov: Journal of medicinal chemistry
• Skrajšan naslov: J. med. chem.
• Založnik: American Chemical Society
• ISSN: 0022-2623
• COBISS.SI-ID: 25763328

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: reakcijski produkti, farmacevtska kemija, peptidi, toksičnost, organske spojine