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

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

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.

• Language: English
• Keywords: reaction products, peptides, proteins, cells, organic compounds, toxicity
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: Str. 7809-7838
• Numbering: Vol. 64, iss. 11
• PID: 20.500.12556/RUL-141424
• UDC: 615.4:54
• ISSN on article: 0022-2623
• DOI: 10.1021/acs.jmedchem.1c00644
• COBISS.SI-ID: 64930051
• Publication date in RUL: 29.09.2022

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 0022-2623
• COBISS.SI-ID: 25763328

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: reakcijski produkti, farmacevtska kemija, peptidi, toksičnost, organske spojine