Synthesis of conformationally constrained 纬-d-glutamyl-meso-diaminopimelic acid derivatives as ligands of nucleotide-binding oligomerization domain protein 1 (Nod1)
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- 作者：沤iga Jakopin ; Martina Gobec ; Jaka Kodela ; Toni Hazdovac ; Irena Mlinari膷-Ra拧膷an ; Marija Sollner Dolenc
- 关键词：Nod1 ; Immunomodulator ; 纬-d-Glutamyl-meso-diaminopimelic acid ; NF-魏B activation ; Immunotoxicity ; Immunostimulant
- 刊名：European Journal of Medicinal Chemistry
- 出版年：November, 2013
- 年：2013
- 卷：69
- 期：Complete
- 页码：232-243
- 全文大小：1122 K
文摘
Nod1, an important member of the pattern recognition receptor family, remains a virtually unexploited target. Harnessing its innate immune stimulatory properties still remains an unfulfilled goal of medicinal chemistry. Nucleotide-binding oligomerization domain protein 1 (Nod1) agonists have been shown to boost the inflammatory responses against pathogenic microbes and could thus constitute a new class of broad spectrum antimicrobial agents. To gain additional insight into the structure/activity relationships of Nod1 agonistic compounds, a series of novel, conformationally constrained 纬-d-glutamyl-meso-diaminopimelic acid (iE-DAP) analogs have been designed and synthesized. Ramos-Blue cells expressing Nod1 were used to screen and validate our compounds for their Nod1-agonist activity. Their immunomodulatory properties were subsequently determined in聽vitro, by evaluating their capacity to induce pro-inflammatory cytokine and chemokine production from human peripheral blood mononuclear cells (PBMC), by themselves and in synergy with lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand. The synthesized iE-DAP analogs were shown to possess immuno-enhancing properties as a result of their potent and specific Nod1-agonistic effect. The activity of the compound exhibiting the greatest capacity to induce pro-inflammatory cytokine release from PBMC surpassed that of lauroyl-纬-d-glutamyl-meso-diaminopimelic acid (C12-iE-DAP).