A short lipopeptide, representative of a new family of immunological adjuvants devoid of sugar

Migliore‐Samour, Danièle; Bouchaudon, J.; Floc'h, F.; Zerial, Aurelio; Ninet, L.; Gh, Werner; Jollès, Pierre

doi:10.1016/0024-3205(80)90351-3

Cited by 49 publications

(26 citation statements)

References 13 publications

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“…The natural tetrapeptide ~A l a -~G l u [~~A~p r n ( G l y ) ] N H z and the natural pentapeptide ~Ala-~Glu[~1.A2pni(Gly)-~Ala] were obtained by extraction of delipidated cells of Streptomyces stimulosus [3,4] strain DS 25556 (NRRL 5776) from RhBne-Poulenc Laboratories. Dipeptide (LAla-DGlu) and muramyl dipeptide were a gift from Hoffmann-La Roche Laboratories (Basel).…”

Section: Preparation Of Peptides and Derivativesmentioning

confidence: 99%

“…Dipeptide (LAla-DGlu) and muramyl dipeptide were a gift from Hoffmann-La Roche Laboratories (Basel). Lauroylation of the dipeptide and pentapeptide was performed as described elsewhere [3,4]. The synthetic lauroyl tetrapeptide N2-[N-(N-laUrOyl-L-alanyl)-y-Dg~utamy~]-N6-g~ycyl-~~,~~-2,6-diaminopime~amic acid was prepared by the RhBne-Poulenc Research Laboratories [3,4].…”

Section: Preparation Of Peptides and Derivativesmentioning

confidence: 99%

“…Their mechanism of action still remains unknown however. Recently we described a new family of natural and/or synthetic short lipopeptides which exhibit immunopotentiating activities although they are devoid of a sugar moiety [3,4]. From crude extracts of a Streptomyces strain possessing nonspecific immunopotentiating effects, a tetrapeptide was isolated and its structure established as ~A l a -~G l u [~~A~p m ( G l y ) ]…”

mentioning

confidence: 99%

“…This peptide was biologically inactive by itself but its chemical coupling with lauric acid gave a substance endowed with adjuvant activities [3,4]. The synthetic lauroyl tetrapeptide lauroyl-r.Ala-uGlu[~~,~~A~pm(Gly)NH2] possessed immunostimulating properties [3,4] similar in many aspects to those observed with N-acetylmuramyl-L-alanyl-i>-isoglutamine (muramyl dipeptide) thus far considered as the minimal adjuvant-active structure of bacterial cell walls [5,6]. Similar features were found in two related substances, the lipodipeptide lauroyi-LAla-DGlu and the lipopentapeptide ~auroyl-~Ala-~Glu[~~A2pm(Gly)-~A~a].…”

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confidence: 99%

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¹H NMR Studies of Natural and Synthetic Immunostimulating Peptides in Aqueous Solution

Delbarre

Migliore‐Samour

Gh³

et al. 1981

European Journal of Biochemistry

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The peptides ~A l a -~G l u (L-alanyl-D-glutamic acid), ~Ala-~Glu[~~A2pm(Gly)]NHz, i.e. N2-(L-ahy1-D-yisoglutaminyl)-N6-glycyl-~~-2,6-diaminopimelic acid, and ~A l a -~G h [~~A z p m ( G l y ) -~A l a ] , i.e. N2-(L-alanyl-i)-y glutamyl)-N6-glycyl-~~-a-2,6-diaminopimelyl-u-alanine, extracted from a Streptornyces strain and their immunostimulating synthetic lauroyl derivatives were studied by 'H NMR spectroscopy at 270 MHz. The chemical shift analysis confirms (a) the sequence of these compounds, (b) the occurrence of a y bond between Glu (or GluNH2) and Azpm, (c) the presence of a carboxamide group on the backbone of the tetrapeptide L A I~-D G I u [ I I A z p m (Gly)]. Temperature and pH studies strongly suggest that the tetrapeptide and pentapeptide exist under \cveral folded conformations characterized by a proximity between the NH; group of Gly and the Glu (or GluNH2) residue. The similarity between the chemical shifts of the corresponding protons in ~A l a -~G l u , lauroyl-LAla-oGlu and muramyl-LAla-DGluNHz shows that the coupling of the dipeptide with a lauroyl or a muramyl group does not induce significant changes in the structure of the peptide moiety. In the lipopeptide series the presence of the lauroyl chain leads to amphipathic substances which form micelles in aqueous solution as shown by the large increase of the proton linewidths. The iminunostimulating properties of this kind of peptide manifest themselves at very low concentration and only after their coupling with a susar or lipid moiety. These features can be interpreted by the formation of mixed complexes between the immunoadjuvants and cell membrane constituents.During the last ten years, a large number of studies has been devoted to bacterial and synthetic immunoadjuvants [1,2], mainly in order to determine their possible therapeutic applications. Their mechanism of action still remains unknown however. Recently we described a new family of natural and/or synthetic short lipopeptides which exhibit immunopotentiating activities although they are devoid of a sugar moiety [3,4]. From crude extracts of a Streptomyces strain possessing nonspecific immunopotentiating effects, a tetrapeptide was isolated and its structure established as ~A l a -~G l u [~~A~p m ( G l y ) ]: the presence of an amide group was detected and arbitrarily attributed to the a' COOH of Azpm. This peptide was biologically inactive by itself but its chemical coupling with lauric acid gave a substance endowed with adjuvant activities [3,4]. The synthetic lauroyl tetrapeptide lauroyl-r.Ala-uGlu[~~,~~A~pm(Gly)NH2] possessed immunostimulating properties [3,4] similar in many aspects to those observed with N-acetylmuramyl-L-alanyl-i>-isoglutamine (muramyl dipeptide) thus far considered as the minimal adjuvant-active structure of bacterial cell walls [5,6]. Similar features were found in two related substances, the lipodipeptide lauroyi-LAla-DGlu and the lipopentapeptide ~auroyl-~Ala-~Glu[~~A2pm(Gly)-~A~a]. The biological activity of these amphipathic compounds seems therefore...

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Section: Preparation Of Peptides and Derivativesmentioning

confidence: 99%

Section: Preparation Of Peptides and Derivativesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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¹H NMR Studies of Natural and Synthetic Immunostimulating Peptides in Aqueous Solution

Delbarre

Migliore‐Samour

Gh³

et al. 1981

European Journal of Biochemistry

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“…several fatty acid-peptide conjugates, due to their amphipathic character. have been shown to possess important biological properties such as the immunostimulating activity [3,4].…”

Section: Introductionmentioning

confidence: 99%

Water‐soluble fatty acid derivatives as acylating agents for reversible lipidization of polypeptides

1995

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A novel method allowing the conjugation of a fatty acid to a peptide or protein in aqueous buffer is described in this paper. L-Cysteinyl 2-pyridyl disulfide (CPD) (III), which was obtained by reacting L-cysteine (I) with 2,2-dithiopyridine (II), was reacted with the N-hydroxysuccinimide ester of palmitic acid (IV) to yield a water-soluble derivative of palmitic acid, termed Pal-CPD (V). Pal-CPD (V) could be reacted with a sulfhydrylcontaining peptide or protein in aqeous buffer to yield the palmitic acid-derivatized conjugate (VI). The palmitic acid-derivatized Bowman-Dirk protease inhibitor (BRI), synthesized using this conjugation method, was demonstrated to have 140-fold higher uptake into Caco-2 cell monolayers compared to native-BBI. The biological activity of the conjugate, as assessed using an in vitro transformation assay, was retained.

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Harnessing the untapped potential of nucleotide‐binding oligomerization domain ligands for cancer immunotherapy

Nabergoj

Mlinarič-Raščan

Jakopin

2018

Medicinal Research Reviews

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In the last decade, cancer immunotherapy has emerged as an effective alternative to traditional therapies such as chemotherapy and radiation. In contrast to the latter, cancer immunotherapy has the potential to distinguish between cancer and healthy cells, and thus to avoid severe and intolerable side‐effects, since the cancer cells are effectively eliminated by stimulated immune cells. The cytosolic nucleotide‐binding oligomerization domains 1 and 2 receptors (NOD1 and NOD2) are important components of the innate immune system and constitute interesting targets in terms of strengthening the immune response against cancer cells. Many NOD ligands have been synthesized, in particular NOD2 agonists that exhibit favorable immunostimulatory and anticancer activity. Among them, mifamurtide has already been approved in Europe by the European Medicine Agency for treating patients with osteosarcoma in combination with chemotherapy after complete surgical removal of the primary tumor. This review is focused on NOD receptors as promising targets in cancer immunotherapy as well as summarizing current knowledge of the various NOD ligands exhibiting antitumor and even antimetastatic activity in vitro and in vivo.

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A short lipopeptide, representative of a new family of immunological adjuvants devoid of sugar

Cited by 49 publications

References 13 publications

¹H NMR Studies of Natural and Synthetic Immunostimulating Peptides in Aqueous Solution

¹H NMR Studies of Natural and Synthetic Immunostimulating Peptides in Aqueous Solution

Water‐soluble fatty acid derivatives as acylating agents for reversible lipidization of polypeptides

Harnessing the untapped potential of nucleotide‐binding oligomerization domain ligands for cancer immunotherapy

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A short lipopeptide, representative of a new family of immunological adjuvants devoid of sugar

Cited by 49 publications

References 13 publications

1H NMR Studies of Natural and Synthetic Immunostimulating Peptides in Aqueous Solution

1H NMR Studies of Natural and Synthetic Immunostimulating Peptides in Aqueous Solution

Water‐soluble fatty acid derivatives as acylating agents for reversible lipidization of polypeptides

Harnessing the untapped potential of nucleotide‐binding oligomerization domain ligands for cancer immunotherapy

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Product

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¹H NMR Studies of Natural and Synthetic Immunostimulating Peptides in Aqueous Solution

¹H NMR Studies of Natural and Synthetic Immunostimulating Peptides in Aqueous Solution