Synthesis of conformationally constrained γ-d-glutamyl-meso-diaminopimelic acid derivatives as ligands of nucleotide-binding oligomerization domain protein 1 (Nod1)

Gobec, Martina; Kodela, Jaka; Hazdovac, Toni; Mlinarič-Raščan, Irena; Dolenc, Marija Sollner

doi:10.1016/j.ejmech.2013.08.022

Cited by 26 publications

(20 citation statements)

References 49 publications

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“…Early efforts in this area involved the chemical modification of core PGN ligands to enhance NOD1 and NOD2 activity. Structure-activity relationship experiments revealed chemical modifications that either attenuate or enhance the stimulatory activity of the NOD1 ligand iE-DAP (Agnihotri et al, 2011; Jakopin et al, 2013) or MDP (Jakopin et al, 2012; Rubino et al, 2013). These studies suggest that new ligands can be developed to enhance NOD1 and NOD2 immunity.…”

Section: Potential For the Therapeutic Modulation Of And Nod1 And Nodmentioning

confidence: 99%

NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

et al. 2014

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Summary The nucleotide-binding oligomerization domain (NOD) proteins, NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce pro-inflammatory and anti-microbial responses. Here we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies suggest several mechanisms to account for the link between NOD2 mutations and susceptibility to Crohn’s disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders.

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Section: Potential For the Therapeutic Modulation Of And Nod1 And Nodmentioning

confidence: 99%

NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

et al. 2014

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“…To do this, we have taken advantage of the selective NOD1 agonist iEDAP [35,36]. To do this, we have taken advantage of the selective NOD1 agonist iEDAP [35,36].…”

Section: Selective Stimulation Of Nod1 Induces Activation Of Nf-κb Anmentioning

confidence: 99%

NOD1 receptor is up-regulated in diabetic human and murine myocardium

et al. 2014

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“…Jakopin et al 3 also examined constraining the orientation of the flexible sp carbon backbone of DAP through the introduction of an alkene. 59 Although no differences in activity were observed for the four derivatives at a single concentration via an NF-jB reporter assay, one compound based on the N,Ndialkyl modification of Agnihotri et al with an alkene between the ɣ and d carbons showed higher activity than its counterpart with a b-ɣ alkene in a cytokine secretion assay. However, this compound was not directly tested against the alkane derivative, so it is unclear whether conformational rigidity of the DAP moiety improves Nod1 activation or is simply tolerated.…”

Section: Chemical Derivatives Of Pg Metabolitesmentioning

confidence: 93%

“…Interestingly, dealkylation of the ɣ‐ d ‐Glu amine with lauryl groups provided an agonist over 10x more potent than C12‐iE‐DAP ( 6 , EC 50 = 0.0015 n m using the NF‐κB reporter assay), but this increase in activity did not extend to other N , N ‐dialkyl compounds. Jakopin et al also examined constraining the orientation of the flexible sp carbon backbone of DAP through the introduction of an alkene . Although no differences in activity were observed for the four derivatives at a single concentration via an NF‐κB reporter assay, one compound based on the N , N ‐dialkyl modification of Agnihotri et al with an alkene between the ɣ and δ carbons showed higher activity than its counterpart with a β‐ɣ alkene in a cytokine secretion assay.…”

Section: Chemical Derivatives Of Pg Metabolitesmentioning

confidence: 99%

Translation of peptidoglycan metabolites into immunotherapeutics

et al. 2019

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The discovery of defined peptidoglycan metabolites that activate host immunity and their specific receptors has revealed fundamental insights into host–microbe recognition and afforded new opportunities for therapeutic development against infection and cancer. In this review, we summarise the discovery of two key peptidoglycan metabolites, γ‐d‐glutamyl‐meso‐diaminopimelic acid (iE‐DAP) and muramyl dipeptide and their respective receptors, Nod1 and Nod2, and review progress towards translating these findings into therapeutic agents. Notably, synthetic derivatives of peptidoglycan metabolites have already yielded approved drugs for chemotherapy‐induced leukopenia and paediatric osteosarcoma; however, the broad effects of peptidoglycan metabolites on host immunity suggest additional translational opportunities for new therapeutics towards other cancers, microbial infections and inflammatory diseases.

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Synthesis of conformationally constrained γ-d-glutamyl-meso-diaminopimelic acid derivatives as ligands of nucleotide-binding oligomerization domain protein 1 (Nod1)

Cited by 26 publications

References 49 publications

NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease

NOD1 receptor is up-regulated in diabetic human and murine myocardium

Translation of peptidoglycan metabolites into immunotherapeutics

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