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

Geetanjali Agnihotri, Rehman Ukani, Subbalakshmi S. Malladi, Hemamali J. Warshakoon, Rajalakshmi Balakrishna, Xinkun Wang, Sunil A. David

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

N-Acyl-γ-glutamyldiaminopimelic 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 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.

Original languageEnglish (US)
Pages (from-to)1490-1510
Number of pages21
JournalJournal of Medicinal Chemistry
Volume54
Issue number5
DOIs
StatePublished - Mar 10 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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