Naslov
Discovery of Nanomolar Desmuramylpeptide Agonists of the Innate Immune Receptor Nucleotide-Binding Oligomerization Domain- Containing Protein 2 (NOD2) Possessing Immunostimulatory Properties

Autori
Gobec, Martina ; Tomašić, Tihomir ; Štimac, Adela ; Frkanec, Ruža ; Trontelj, Jurij ; Anderluh, Marko ; Mlinarič-Raščan, Irena ; Jakopin, Žiga

Izvornik
Journal of medicinal chemistry (0022-2623) 61 (2018), 7; 2707-2724

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Muramyl dipeptide, immunomodulator, desmuramylpeptide, NOD2 agonist, immunostimulant, adjuvant

Sažetak
Muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, has long been known as the smallest fragment possessing adjuvant activity, on the basis of its agonistic action on the nucleotide-binding oligomerization domain- containing protein 2 (NOD2). There is a pressing need for novel adjuvants and NOD2 agonists provide an untapped source of potential candidates. Here, we report the design, synthesis and characterization of a series of novel acyl tripeptides. A pivotal structural element for molecular recognition by NOD2 has been identified, culminating in the discovery of compound 9, the most potent desmuramylpeptide NOD2 agonist to date. Compound 9 augmented pro- inflammatory cytokine release from human peripheral blood mononuclear cells in synergy with lipopolysaccharide. Furthermore, it was able to induce ovalbumin- specific IgG titers in a mouse model of adjuvancy. These findings provide deeper insights into the structural requirements of desmuramylpeptides for NOD2-activation and highlight the potential use of NOD2 agonists as adjuvants for vaccines.

Izvorni jezik
Engleski

POVEZANOST RADA