Structure-activity relationships in nucleotide oligomerization domain 1 (Nod1) agonistic γ-glutamyldiaminopimelic acid derivatives

J Med Chem. 2011 Mar 10;54(5):1490-510. doi: 10.1021/jm101535e. Epub 2011 Feb 7.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adjuvants, Immunologic / chemical synthesis
  • Adjuvants, Immunologic / chemistry
  • Adjuvants, Immunologic / pharmacology
  • CD11b Antigen / biosynthesis
  • Diaminopimelic Acid / analogs & derivatives*
  • Diaminopimelic Acid / chemical synthesis
  • Diaminopimelic Acid / chemistry
  • Diaminopimelic Acid / pharmacology
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • In Vitro Techniques
  • Interleukins / biosynthesis
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Membrane Glycoproteins / biosynthesis
  • NF-kappa B / biosynthesis
  • Nod1 Signaling Adaptor Protein / agonists*
  • Receptors, Immunologic / biosynthesis
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triggering Receptor Expressed on Myeloid Cells-1
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / biosynthesis

Substances

  • Adjuvants, Immunologic
  • CD11b Antigen
  • Interleukins
  • Membrane Glycoproteins
  • NF-kappa B
  • NOD1 protein, human
  • Nod1 Signaling Adaptor Protein
  • Receptors, Immunologic
  • TREM1 protein, human
  • Triggering Receptor Expressed on Myeloid Cells-1
  • Diaminopimelic Acid
  • N(2)-(gamma-D-glutamyl)-meso-2,2'-diaminopimelic acid
  • p38 Mitogen-Activated Protein Kinases