title: Structure-activity relationships in nucleotide oligomerization domain 1 (Nod1) agonistic γ-glutamyldiaminopimelic acid derivatives.
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.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, 2030 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Agnihotri
authors.forename: Rehman
authors.initials: R
authors.lastname: Ukani
authors.forename: Subbalakshmi S
authors.initials: SS
authors.lastname: Malladi
authors.forename: Hemamali J
authors.initials: HJ
authors.lastname: Warshakoon
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Balakrishna
authors.forename: Xinkun
authors.initials: X
authors.lastname: Wang
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D039481:CD11b Antigen / Q000096:biosynthesis; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D066298:In Vitro Techniques; D007378:Interleukins / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D016328:NF-kappa B / Q000096:biosynthesis; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists*; D011971:Receptors, Immunologic / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
chemical_list: D000276:Adjuvants, Immunologic; D039481:CD11b Antigen; D007378:Interleukins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D003960:Diaminopimelic Acid; C034331:N(2)-(gamma-D-glutamyl)-meso-2,2'-diaminopimelic acid; D048051:p38 Mitogen-Activated Protein Kinases