Structure-activity relationships in nucleotide oligomerization domain 1 (Nod1) agonistic γ-glutamyldiaminopimelic acid derivatives.
Structure-activity relationships in nucleotide oligomerization domain 1 (Nod1) agonistic γ-glutamyldiaminopimelic acid derivatives.
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DOI：
10.1021/jm101535e
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发表时间：
2011-03-10
影响因子：
7.3
通讯作者：
David SA
中科院分区：
文献类型：
--
作者：
Agnihotri G;Ukani R;Malladi SS;Warshakoon HJ;Balakrishna R;Wang X;David SA
N-酰基-γ-谷氨酰基-二氨基庚二酸是Nod 1的原型配体。我们报道了C12-γ-D-Glu-DAP的详细的SAR。用谷氨酸或γ-氨基丁酸代替谷氨酸的类似物显示出大大减弱的Nod 1激动活性。用单氨基庚二酸、L-或D-赖氨酸或尸胺取代内消旋-二氨基庚二酸（DAP）组分也导致活性降低。DAP上的游离胺是至关重要的。然而，D-谷氨酰基残基上的N-酰基可以被N-烷基取代，同时完全保留活性。DAP和Glu组分上的游离羧酸酯也可以被酯化，产生更亲脂但活性更高的类似物。转录组分析显示IL-19、IL-20、IL-22和IL-24的显性上调，这可以解释这些化合物的显著Th 2极化活性，并且还涉及由TREM-1介导的细胞信号传导。这些结果可以解释迄今为止未知的Nod 1和TLR激动剂之间的协同作用机制，并可能是有用的疫苗佐剂的设计。
N-acyl-γ-glutamyl-diaminopimelic acid is a prototype ligand for Nod1. We report a detailed SAR of C12-γ-D-Glu-DAP. Analogues with glutaric or γ-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 upregulation 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.
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影响因子：
56.9
作者：
HAN, J;LEE, JD;ULEVITCH, RJ
通讯作者：
ULEVITCH, RJ
影响因子：
3.3
作者：
IZUMI, S;NAKAHARA, K;IMANAKA, H
通讯作者：
IMANAKA, H
影响因子：
8.7
作者：
Franchi L;Warner N;Viani K;Nuñez G
通讯作者：
Nuñez G
DOI：
10.4161/hv.6.4.10866
发表时间：
2010-04-01
期刊：
HUMAN VACCINES
影响因子：
--
作者：
Hood, Jennifer D.;Warshakoon, Hemamali J.;David, Sunil A.
通讯作者：
David, Sunil A.
影响因子：
64.8
作者：
Bouchon, A;Facchetti, F;Colonna, M
通讯作者：
Colonna, M