Document Detail


Structure-activity relationships in nucleotide oligomerization domain 1 (Nod1) agonistic γ-glutamyldiaminopimelic acid derivatives.
MedLine Citation:
PMID:  21299227     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Geetanjali Agnihotri; Rehman Ukani; Subbalakshmi S Malladi; Hemamali J Warshakoon; Rajalakshmi Balakrishna; Xinkun Wang; Sunil A David
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural     Date:  2011-02-07
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  54     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-03-03     Completed Date:  2011-06-06     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1490-510     Citation Subset:  IM    
Affiliation:
Department of Medicinal Chemistry, University of Kansas, 2030 Becker Drive, Lawrence, Kansas 66047, United States.
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MeSH Terms
Descriptor/Qualifier:
Adjuvants, Immunologic / chemical synthesis,  chemistry,  pharmacology
Antigens, CD11b / biosynthesis
Diaminopimelic Acid / analogs & derivatives*,  chemical synthesis,  chemistry,  pharmacology
Gene Expression Profiling
HEK293 Cells
Humans
Immunity, Innate
Interleukins / biosynthesis
Leukocytes, Mononuclear / drug effects,  metabolism
Membrane Glycoproteins / biosynthesis
NF-kappa B / biosynthesis
Nod1 Signaling Adaptor Protein / agonists*
Receptors, Immunologic / biosynthesis
Stereoisomerism
Structure-Activity Relationship
Up-Regulation
p38 Mitogen-Activated Protein Kinases / biosynthesis
Grant Support
ID/Acronym/Agency:
HHSN272200900033C/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Adjuvants, Immunologic; 0/Antigens, CD11b; 0/Interleukins; 0/Membrane Glycoproteins; 0/NF-kappa B; 0/NOD1 protein, human; 0/Nod1 Signaling Adaptor Protein; 0/Receptors, Immunologic; 0/TREM1 protein, human; 583-93-7/Diaminopimelic Acid; 71974-09-9/N(2)-(gamma-D-glutamyl)-meso-2,2'-diaminopimelic acid; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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