Structure鈭扐ctivity Relationships in Nucleotide Oligomerization Domain 1 (Nod1) Agonistic 纬-Glutamyldiaminopimelic Acid Derivatives

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• 作者：Geetanjali Agnihotri ; Rehman Ukani ; Subbalakshmi S. Malladi ; Hemamali J. Warshakoon ; Rajalakshmi Balakrishna ; Xinkun Wang ; Sunil A. David
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1490-1510
• 全文大小：1497K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

N-Acyl-纬-glutamyldiaminopimelic acid is a prototype ligand for Nod1. We report a detailed SAR of C₁₂-纬-d-Glu-DAP. Analogues with glutaric or 纬-aminobutyric acid replacing the glutamic acid show greatly attenuated Nod1-agonistic activity. Substitution of the meso-diaminopimelic (DAP) acid component with monoaminopimelic acid, l- or d-lysine, or cadaverine also results in reduced activity. The free amine on DAP is crucial. However, the N-acyl group on the d-glutamyl residue can be substituted with N-alkyl groups with full preservation of activity. The free carboxylates on the DAP and Glu components can also be esterified, resulting in more lipophilic but active analogues. Transcriptomal profiling showed a dominant up-regulation of IL-19, IL-20, IL-22, and IL-24, which may explain the pronounced Th2-polarizing activity of these compounds and also implicate cell signaling mediated by TREM-1. These results may explain the hitherto unknown mechanism of synergy between Nod1 and TLR agonists and are likely to be useful in designing vaccine adjuvants.