Abstract
N-acyl-γ-glutamyldiaminopimelic acid is a prototype ligand for Nod1. We report a detailed SAR of C(12)-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 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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adjuvants, Immunologic / chemical synthesis
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Adjuvants, Immunologic / chemistry
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Adjuvants, Immunologic / pharmacology
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CD11b Antigen / biosynthesis
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Diaminopimelic Acid / analogs & derivatives*
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Diaminopimelic Acid / chemical synthesis
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Diaminopimelic Acid / chemistry
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Diaminopimelic Acid / pharmacology
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Gene Expression Profiling
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HEK293 Cells
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Humans
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Immunity, Innate
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In Vitro Techniques
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Interleukins / biosynthesis
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Membrane Glycoproteins / biosynthesis
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NF-kappa B / biosynthesis
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Nod1 Signaling Adaptor Protein / agonists*
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Receptors, Immunologic / biosynthesis
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Stereoisomerism
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Structure-Activity Relationship
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Triggering Receptor Expressed on Myeloid Cells-1
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Up-Regulation
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p38 Mitogen-Activated Protein Kinases / biosynthesis
Substances
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Adjuvants, Immunologic
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CD11b Antigen
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Interleukins
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Membrane Glycoproteins
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NF-kappa B
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NOD1 protein, human
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Nod1 Signaling Adaptor Protein
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Receptors, Immunologic
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TREM1 protein, human
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Triggering Receptor Expressed on Myeloid Cells-1
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Diaminopimelic Acid
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N(2)-(gamma-D-glutamyl)-meso-2,2'-diaminopimelic acid
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p38 Mitogen-Activated Protein Kinases