Structure-Activity Relationships in Nucleotide Oligomerization Domain-1 (Nod1)-Agonistic γ-Glutamyl-diaminopimelic Acid Derivatives
Malladi, Subbalakshmi S.
Warshakoon, Hemamali J.
David, Sunil A.
American Chemical Society
Scholarly/refereed, author accepted manuscript
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm101535e.
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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.
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
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