Structural Fine-Tuning of Desmuramylpeptide NOD2 Agonists Defines Their 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 and adjuvant properties. We identified two promising compounds: , a potent nanomolar NOD2 agonist, and the more lipophilic , which shows superior adjuvant activity . 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 additionally enhanced the cytotoxic activity of peripheral blood mononuclear cells against malignant cells. The C lipophilic tail of is identified as a pivotal structural element that confers adjuvant activity in conjunction with a liposomal delivery system. Accordingly, liposome-encapsulated 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.