N2-(.gamma.-D-glutamyl)-meso-2-(L),2'(D)-diaminopimelic acid as the minimal prerequisite structure of FK-156: its acyl derivatives with potent immunostimulating activity

Kitaura, Yoshihiko; Nakaguchi, Osamu; Takeno, Hidekazu; Okada, Satoshi; Yonishi, S.; Hemmi, Keiji; Mori, Joh; Senoh, Hachiro; Mine, Yasuhiro; Hashimoto, Masashi

doi:10.1021/jm00346a001

Cited by 38 publications

(18 citation statements)

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“…Similar results were observed using chemically synthesized TCT (data not shown). Transfection of synthetic desmuramylpeptide, a peptidoglycan fragment containing DAP, FK156 ( d -lactyl- l -Ala-γ- d -Glu-meso-DAP-Gly)36, or its derivative, FK565 (haptanoyl-γ- d -Glu-meso-DAP- d -Ala), did not increase the number of GFP-LC3 dots in S2 cells expressing PGRP-LE (data not shown). Correlative FM-EM analysis revealed that the TCT-induced GFP-LC3–expressing structures have double-membrane structures typical of autophagosomes (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 95%

Autophagic control of listeria through intracellular innate immune recognition in drosophila

et al. 2008

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Autophagy, an evolutionally conserved homeostatic process for catabolizing cytoplasmic components, has been implicated in the elimination of intracellular pathogens during mammalian innate immune responses. However, the mechanisms underlying cytoplasmic infection-induced autophagy, and the role of autophagy in host survival against intracellular pathogens are unknown. Here we report that in drosophila, recognition of diaminopimelic acid-type peptidoglycans by the pattern recognition receptor PGRP-LE is crucial for the induction of autophagy, and that autophagy prevents the intracellular growth of Listeria monocytogenes and promotes host survival against this infection. Autophagy induction occurs independently of the Toll and IMD innate signaling pathways. These findings define a clear pathway leading from the intracellular pattern recognition receptors to the induction of autophagy to host defense.

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Section: Resultsmentioning

confidence: 95%

Autophagic control of listeria through intracellular innate immune recognition in drosophila

et al. 2008

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“…This point is illustrated by the adjuvanticity, pyrogenicity, and somnogenicity of MDP (6,13,15). In contrast, the dipeptide y-D-Glu-meso-A2pm is the smallest active fragment of desmuramyl peptide FK-156 as assessed by phagocytic activity in DDY mice, stimulation of delayedtype hypersensitivity, and protective effect against Escherichia coli infection in mice (32). These results indicate that there are at least two different sets of structure-activity relationships to be described for muramyl and desmuramyl peptides.…”

Section: Discussionmentioning

confidence: 99%

Bordetella pertussis tracheal cytotoxin and other muramyl peptides: distinct structure-activity relationships for respiratory epithelial cytopathology.

Luker

Collier

Kolodziej

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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Tracheal cytotoxin (TCT) is a disaccharidetetrapeptide released by Bordetella pertussis, the causative agent of pertussis (whooping cough). We have previously determined the structure of TCT to be GIcNAc-1,6-anhydroMurNAc-L-Ala-y-D-Glu-meso-A2pm-D-Ala, where MurNAc = N-acetylmuramic acid and A2pm = diaminopimelic acid. Purified TCT reproduces the respiratory cytopathology observed during pertussis, including ciliostasis and extrusion of ciliated cells. We have tested structural analogs of TCT for their ability to reproduce native TCT toxicity in explanted hamster tracheal tissue and hamster trachea epithelial (HTE) cell cultures. Other investigators have evaluated many of these analogs, which are muramyl or desmuramyl peptides, for muramyl peptide activities such as immunopotentiation, induction of slow-wave sleep, and pyrogenicity. Four desmuramyl peptides were produced in our laboratory from B. pertussis peptidoglycan or by chemical synthesis, including unusual peptides containing a-aminopimelic acid in place of A2pm. Based on the relative ability of compounds to inhibit DNA synthesis in HTE cells, truncated analogs lacking A2pm entirely or lacking only the side-chain amine or carboxyl group of A2pm were less active than TCT by a factor of at least 1000. All active analogs included a native or near-native peptide moiety, independent of the presence, absence, or substitution of the sugar moiety. We conclude that the structural requirements for TCT toxicity differ considerably from those for most other muramyl peptide activities, in that the disaccharide moiety is irrelevant for toxicity and both the free amino and carboxyl groups of the A2pm side chain are required for activity.Tracheal cytotoxin (TCT) is a low molecular weight glycopeptide released during logarithmic-phase growth of Bordetella pertussis. It is the only B. pertussis product that reproduces the respiratory cytopathology observed during pertussis (whooping cough) (1). This pathology includes ciliostasis and specific extrusion of ciliated cells from the respiratory epithelium. In the absence of ciliary activity, coughing becomes the only way to clear the airways of accumulating mucus, bacteria, and inflammatory debris. Thus, TCT-mediated destruction of ciliated cells may trigger the violent coughing episodes symptomatic of pertussis. In addition, the absence of a ciliary clearance mechanism predisposes patients to secondary pulmonary infections, the primary cause of pertussis mortality (2).We have previously reported the purification of TCT by reversed-phase HPLC (RP-HPLC) and determined its structure by fast atom bombardment (FAB)-MS to be GlcNAc-1,6-anhydro-MurNAc-L-Ala-y-D-Glu-meso-A2pm-D-Ala (Fig. 1) (3), where MurNAc is N-acetylmuramic acid and A2pm is diaminopimelic acid. TCT belongs to a family of compounds known as muramyl peptides, which have many biological activities including adjuvanticity, somnogenicity, and pyrogenicity (4-6). Naturally occurring muramyl peptides are of bacterial origin; they are fragments of peptidoglycan, t...

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“…(2)) [22]. They also reported that the minimum active entity of DMP was γ-D-glutamyl-meso-DAP [23], which was recently demonstrated to be a minimum NOD1-agonist and was designated as iE-DAP (Fig. (2)).…”

Section: Intracellular Pgn Receptors Nod1 and Nod2mentioning

confidence: 99%

Enhancement of TLR-Mediated Innate Immune Responses by Peptidoglycans through NOD Signaling

Takada

Uehara

2006

CPD

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Toll-like receptors (TLRs) recognize common motifs, pathogen-associated molecular patterns (PAMPs), in microorganisms. Bacterial PAMPs are mainly distributed on cell-surfaces. Peptidoglycans (PGNs) are ubiquitous constituents of bacterial cell walls. Muramyldipeptide (MDP; N-acetylmuramyl-l-alanyl-d-isoglutamine) is a common and key structure of PGNs and exhibits most the of bioactivities of PGNs. Recently, the intracellular receptor for MDP was revealed to be NOD2. Another bioactive moiety of PGNs, diaminopimelic acid (DAP) containing desmuramylpeptides (DMPs), senses another intracellular receptor, NOD1. MDP-primed mice exhibited hyper-responses to endotoxin and other bacterial components, which sense Toll-like receptors (TLRs), although MDP itself does not exhibit apparent activity in mice. On the other hand, DMPs exhibited definite activity in mice, and the most powerful DMP, FK565, exhibited stronger priming activity than MDP. In human monocytic cells, both MDP and DMPs exhibited definite activities; marked synergistic interleukin (IL)-8 secretion was induced by DMPs and MDP in combination with synthetic TLR agonists, and suppression of the mRNA expressions of NOD1 and NOD2, respectively, by RNA interference specifically inhibited synergistic IL-8 secretion. In human dendritic cells (DCs), synergistic T helper type 1 responses are induced by combined stimulations of synthetic NOD and TLR agonists. Considering these findings altogether, in host-bacteria interactions, host cells should recognize bacteria via both TLRs and NODs, which might induce synergistic innate and adaptive immune responses.

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N2-(.gamma.-D-glutamyl)-meso-2-(L),2'(D)-diaminopimelic acid as the minimal prerequisite structure of FK-156: its acyl derivatives with potent immunostimulating activity

Cited by 38 publications

References 0 publications

Autophagic control of listeria through intracellular innate immune recognition in drosophila

Autophagic control of listeria through intracellular innate immune recognition in drosophila

Bordetella pertussis tracheal cytotoxin and other muramyl peptides: distinct structure-activity relationships for respiratory epithelial cytopathology.

Enhancement of TLR-Mediated Innate Immune Responses by Peptidoglycans through NOD Signaling

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