Structure-activity relationships in nucleotide oligomerization domain 1 (Nod1) agonistic γ-glutamyldiaminopimelic acid derivatives
| Autor: | Rajalakshmi Balakrishna, Hemamali J. Warshakoon, Rehman Ukani, Sunil A. David, Subbalakshmi S. Malladi, Geetanjali Agnihotri, Xinkun Wang |
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| Rok vydání: | 2011 |
| Předmět: |
Cell signaling
Stereochemistry In Vitro Techniques Diaminopimelic Acid p38 Mitogen-Activated Protein Kinases Article chemistry.chemical_compound Structure-Activity Relationship Adjuvants Immunologic Nod1 Signaling Adaptor Protein Drug Discovery NOD1 Humans Nucleotide Receptors Immunologic chemistry.chemical_classification Cadaverine Innate immune system CD11b Antigen Membrane Glycoproteins Gene Expression Profiling Interleukins NF-kappa B Stereoisomerism Glutamic acid Immunity Innate Triggering Receptor Expressed on Myeloid Cells-1 Up-Regulation HEK293 Cells chemistry Biochemistry Leukocytes Mononuclear Molecular Medicine Amine gas treating Diaminopimelic acid |
| Zdroj: | Journal of medicinal chemistry. 54(5) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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