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Structure-Activity Relationships in Nucleotide Oligomerization Domain-1 (Nod1)-Agonistic γ-Glutamyl-diaminopimelic Acid Derivatives
dc.contributor.author | Agnihotri, Geetanjali | |
dc.contributor.author | Ukani, Rehman | |
dc.contributor.author | Malladi, Subbalakshmi S. | |
dc.contributor.author | Warshakoon, Hemamali J. | |
dc.contributor.author | Balakrishna, Rajalakshmi | |
dc.contributor.author | Wang, Xinkun | |
dc.contributor.author | David, Sunil A. | |
dc.date.accessioned | 2017-04-12T14:25:22Z | |
dc.date.available | 2017-04-12T14:25:22Z | |
dc.date.issued | 2011-03-10 | |
dc.identifier.citation | Agnihotri, G., Ukani, R., Malladi, S. S., Warshakoon, H. J., Balakrishna, R., Wang, X., & David, S. A. (2011). Structure-Activity Relationships in Nucleotide Oligomerization Domain-1 (Nod1)-Agonistic γ-Glutamyl-diaminopimelic Acid Derivatives. Journal of Medicinal Chemistry, 54(5), 1490–1510. http://doi.org/10.1021/jm101535e | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/23625 | |
dc.description.abstract | N-acyl-γ-glutamyl-diaminopimelic 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 upregulation 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. | en_US |
dc.publisher | American Chemical Society | en_US |
dc.rights | This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm101535e. | en_US |
dc.subject | Nod1 | en_US |
dc.subject | iE-DAP | en_US |
dc.subject | Diaminopimelic acid | en_US |
dc.subject | Vaccine adjuvants | en_US |
dc.subject | Innate immunity | en_US |
dc.title | Structure-Activity Relationships in Nucleotide Oligomerization Domain-1 (Nod1)-Agonistic γ-Glutamyl-diaminopimelic Acid Derivatives | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Agnihotri, Geetanjali | |
kusw.kuauthor | Ukani, Rehman | |
kusw.kuauthor | Malladi, Subbalakshmi S. | |
kusw.kuauthor | Warshakoon, Hemamali J. | |
kusw.kuauthor | Balakrishna, Rajalakshmi | |
kusw.kuauthor | Wang, Xinkun | |
kusw.kuauthor | David, Sunil A. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1021/jm101535e | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-1377-0509 | |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |