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Structure-Activity Relationships in Nucleotide Oligomerization Domain-1 (Nod1)-Agonistic γ-Glutamyl-diaminopimelic Acid Derivatives
Agnihotri, Geetanjali Ukani, Rehman Malladi, Subbalakshmi S. Warshakoon, Hemamali J. Balakrishna, Rajalakshmi Wang, Xinkun David, Sunil A.
Agnihotri, Geetanjali
Ukani, Rehman
Malladi, Subbalakshmi S.
Warshakoon, Hemamali J.
Balakrishna, Rajalakshmi
Wang, Xinkun
David, Sunil A.
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Abstract
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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Date
2011-03-10
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American Chemical Society
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Keywords
Nod1, iE-DAP, Diaminopimelic acid, Vaccine adjuvants, Innate immunity
Citation
Agnihotri, G., Ukani, R., Malladi, S. S., Warshakoon, H. J., Balakrishna, R., Wang, X., & David, S. A. (2011). Structure-Activity Relationships in Nucleotide Oligomerization Domain-1 (Nod1)-Agonistic γ-Glutamyl-diaminopimelic Acid Derivatives. Journal of Medicinal Chemistry, 54(5), 1490–1510. http://doi.org/10.1021/jm101535e