Distinctive immune signatures driven by structural alterations in desmuramylpeptide NOD2 agonists

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

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 (EC$_{50}$ = 4.6 nM), exhibiting an almost 17-fold enhancement in potency compared to its unsubstituted counterpart 1 (EC$_{50}$ = 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.

• Jezik: Angleški jezik
• Ključne besede: agonists, cells, peptides, proteins, reaction products, 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: 2024
• Št. strani: Str. 17585–17607
• Številčenje: Vol. 67, iss. 19
• PID: 20.500.12556/RUL-163778
• UDK: 615.9+615.375
• ISSN pri članku: 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01577
• COBISS.SI-ID: 209432835
• Datum objave v RUL: 10.10.2024

Gradivo je del revije

• Naslov: Journal of medicinal chemistry
• Skrajšan naslov: J. med. chem.
• Založnik: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

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: agonisti, celice, peptidi in proteini, reakcijski produkti, toksičnost, imunomodulatorji