hCXCR1 and hCXCR2 antagonists derived from combinatorial peptide libraries.
Identifieur interne : 000143 ( Main/Exploration ); précédent : 000142; suivant : 000144hCXCR1 and hCXCR2 antagonists derived from combinatorial peptide libraries.
Auteurs : Mehdi Houimel [Tunisie] ; Luca MazzucchelliSource :
- Cytokine [ 1096-0023 ] ; 2012.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Bactériophages (effets des médicaments et des substances chimiques), Banque de peptides (MeSH), Calcium (métabolisme), Chimiotaxie (effets des médicaments et des substances chimiques), Chromatographie d'affinité (MeSH), Données de séquences moléculaires (MeSH), Espace intracellulaire (effets des médicaments et des substances chimiques), Espace intracellulaire (métabolisme), Fixation compétitive (effets des médicaments et des substances chimiques), Granulocytes neutrophiles (cytologie), Granulocytes neutrophiles (effets des médicaments et des substances chimiques), Granulocytes neutrophiles (métabolisme), Humains (MeSH), Liaison aux protéines (effets des médicaments et des substances chimiques), Peptides (composition chimique), Peptides (pharmacologie), Récepteurs à l'interleukine-8A (antagonistes et inhibiteurs), Récepteurs à l'interleukine-8A (composition chimique), Récepteurs à l'interleukine-8B (antagonistes et inhibiteurs), Récepteurs à l'interleukine-8B (composition chimique), Souris (MeSH), Séquence d'acides aminés (MeSH), Techniques de chimie combinatoire (méthodes), Transfection (MeSH).
- MESH :
- antagonistes et inhibiteurs : Récepteurs à l'interleukine-8A, Récepteurs à l'interleukine-8B.
- composition chimique : Peptides, Récepteurs à l'interleukine-8A, Récepteurs à l'interleukine-8B.
- cytologie : Granulocytes neutrophiles.
- effets des médicaments et des substances chimiques : Bactériophages, Chimiotaxie, Espace intracellulaire, Fixation compétitive, Granulocytes neutrophiles, Liaison aux protéines.
- métabolisme : Calcium, Espace intracellulaire, Granulocytes neutrophiles.
- méthodes : Techniques de chimie combinatoire.
- pharmacologie : Peptides.
- Animaux, Banque de peptides, Chromatographie d'affinité, Données de séquences moléculaires, Humains, Souris, Séquence d'acides aminés, Transfection.
English descriptors
- KwdEn :
- Amino Acid Sequence (MeSH), Animals (MeSH), Bacteriophages (drug effects), Binding, Competitive (drug effects), Calcium (metabolism), Chemotaxis (drug effects), Chromatography, Affinity (MeSH), Combinatorial Chemistry Techniques (methods), Humans (MeSH), Intracellular Space (drug effects), Intracellular Space (metabolism), Mice (MeSH), Molecular Sequence Data (MeSH), Neutrophils (cytology), Neutrophils (drug effects), Neutrophils (metabolism), Peptide Library (MeSH), Peptides (chemistry), Peptides (pharmacology), Protein Binding (drug effects), Receptors, Interleukin-8A (antagonists & inhibitors), Receptors, Interleukin-8A (chemistry), Receptors, Interleukin-8B (antagonists & inhibitors), Receptors, Interleukin-8B (chemistry), Transfection (MeSH).
- MESH :
- chemical , antagonists & inhibitors : Receptors, Interleukin-8A, Receptors, Interleukin-8B.
- chemical , chemistry : Peptides, Receptors, Interleukin-8A, Receptors, Interleukin-8B.
- chemical , metabolism : Calcium.
- cytology : Neutrophils.
- drug effects : Bacteriophages, Binding, Competitive, Chemotaxis, Intracellular Space, Neutrophils, Protein Binding.
- metabolism : Intracellular Space, Neutrophils.
- methods : Combinatorial Chemistry Techniques.
- chemical , pharmacology : Peptides.
- Amino Acid Sequence, Animals, Chromatography, Affinity, Humans, Mice, Molecular Sequence Data, Peptide Library, Transfection.
Abstract
The human CXCL8 plays important roles in inflammation by activation of neutrophils through the hCXCR1 and hCXCR2 receptors. The role of hCXCR1 and hCXCR2 in the pathogenesis of inflammatory responses has encouraged the development of antagonists of these receptors. In this study, we used phage display peptide libraries to identify peptides antagonists that block the interactions between hCXCL8 and hCXCR1/2. Two linear hexapeptides (MSRAKE and CAKELR) and two disulfide-constrained hexapeptides (CLRSGRFC and CLPWKENC) were recovered by panning phage libraries on hCXCR1- and hCXCR2-transfected murine pre-B cells after specific elution with hCXCL8. Sequence analysis revealed homology between the linear hexapeptides and the N-terminal domain (1-SAKELR-6), whereas the constrained peptides are composed of non-contiguous amino acids mimicking spatial structure on the surface of folded C-terminal portion of hCXCL8 (50-CLDPKENWVQRVVEKFLKRAENS-72). The synthetic linear and structurally constrained peptides competed for (125)I-hCXCL8 binding to hCXCR1 and hCXCR2 (IC(50) comprised between 10 and 100μM). Furthermore, they inhibited the intracellular calcium flux and the migration of hCXCR1/hCXCR2 transfectants; and desensitized hCXCR1 and hCXCR2 receptors on neutrophils, reducing their chemotactic responses induced by ELR-CXC chemokines (hCXCL8, hCXCL1, hCXCL2, hCXCL3, and hCXCL5). To better characterize the residues required for hCXCL8 binding, we identified three linear peptides MLRQTR, HASILP and KKEPWI specific to hCXCL8. These peptides similarly displaced the binding of (125)I-hCXCL8 to hCXCR1 (IC(50) ranging from 8.5 to 10μM) in a dose-dependent manner, inhibited hCXCL8 induced increases in the intracellular calcium, and migration of hCXCR1- and hCXCR2-transfected cells. The identified peptides could be used as antagonists of hCXCL8-induced activities related to its interaction with hCXCR1 and hCXCR2 receptors and may help in the design of new anti-inflammatory therapeutic molecules.
DOI: 10.1016/j.cyto.2011.11.022
PubMed: 22189418
Affiliations:
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Le document en format XML
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<wicri:regionArea>Laboratoire d'Immunologie, Vaccinologie et Génétique Moléculaire, Institut Pasteur de Tunis</wicri:regionArea>
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<author><name sortKey="Mazzucchelli, Luca" sort="Mazzucchelli, Luca" uniqKey="Mazzucchelli L" first="Luca" last="Mazzucchelli">Luca Mazzucchelli</name>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence (MeSH)</term>
<term>Animals (MeSH)</term>
<term>Bacteriophages (drug effects)</term>
<term>Binding, Competitive (drug effects)</term>
<term>Calcium (metabolism)</term>
<term>Chemotaxis (drug effects)</term>
<term>Chromatography, Affinity (MeSH)</term>
<term>Combinatorial Chemistry Techniques (methods)</term>
<term>Humans (MeSH)</term>
<term>Intracellular Space (drug effects)</term>
<term>Intracellular Space (metabolism)</term>
<term>Mice (MeSH)</term>
<term>Molecular Sequence Data (MeSH)</term>
<term>Neutrophils (cytology)</term>
<term>Neutrophils (drug effects)</term>
<term>Neutrophils (metabolism)</term>
<term>Peptide Library (MeSH)</term>
<term>Peptides (chemistry)</term>
<term>Peptides (pharmacology)</term>
<term>Protein Binding (drug effects)</term>
<term>Receptors, Interleukin-8A (antagonists & inhibitors)</term>
<term>Receptors, Interleukin-8A (chemistry)</term>
<term>Receptors, Interleukin-8B (antagonists & inhibitors)</term>
<term>Receptors, Interleukin-8B (chemistry)</term>
<term>Transfection (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Bactériophages (effets des médicaments et des substances chimiques)</term>
<term>Banque de peptides (MeSH)</term>
<term>Calcium (métabolisme)</term>
<term>Chimiotaxie (effets des médicaments et des substances chimiques)</term>
<term>Chromatographie d'affinité (MeSH)</term>
<term>Données de séquences moléculaires (MeSH)</term>
<term>Espace intracellulaire (effets des médicaments et des substances chimiques)</term>
<term>Espace intracellulaire (métabolisme)</term>
<term>Fixation compétitive (effets des médicaments et des substances chimiques)</term>
<term>Granulocytes neutrophiles (cytologie)</term>
<term>Granulocytes neutrophiles (effets des médicaments et des substances chimiques)</term>
<term>Granulocytes neutrophiles (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Liaison aux protéines (effets des médicaments et des substances chimiques)</term>
<term>Peptides (composition chimique)</term>
<term>Peptides (pharmacologie)</term>
<term>Récepteurs à l'interleukine-8A (antagonistes et inhibiteurs)</term>
<term>Récepteurs à l'interleukine-8A (composition chimique)</term>
<term>Récepteurs à l'interleukine-8B (antagonistes et inhibiteurs)</term>
<term>Récepteurs à l'interleukine-8B (composition chimique)</term>
<term>Souris (MeSH)</term>
<term>Séquence d'acides aminés (MeSH)</term>
<term>Techniques de chimie combinatoire (méthodes)</term>
<term>Transfection (MeSH)</term>
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<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Receptors, Interleukin-8A</term>
<term>Receptors, Interleukin-8B</term>
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<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Peptides</term>
<term>Receptors, Interleukin-8A</term>
<term>Receptors, Interleukin-8B</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Calcium</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Récepteurs à l'interleukine-8A</term>
<term>Récepteurs à l'interleukine-8B</term>
</keywords>
<keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Peptides</term>
<term>Récepteurs à l'interleukine-8A</term>
<term>Récepteurs à l'interleukine-8B</term>
</keywords>
<keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Granulocytes neutrophiles</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Neutrophils</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Bacteriophages</term>
<term>Binding, Competitive</term>
<term>Chemotaxis</term>
<term>Intracellular Space</term>
<term>Neutrophils</term>
<term>Protein Binding</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Bactériophages</term>
<term>Chimiotaxie</term>
<term>Espace intracellulaire</term>
<term>Fixation compétitive</term>
<term>Granulocytes neutrophiles</term>
<term>Liaison aux protéines</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Intracellular Space</term>
<term>Neutrophils</term>
</keywords>
<keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Combinatorial Chemistry Techniques</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Calcium</term>
<term>Espace intracellulaire</term>
<term>Granulocytes neutrophiles</term>
</keywords>
<keywords scheme="MESH" qualifier="méthodes" xml:lang="fr"><term>Techniques de chimie combinatoire</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Peptides</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Peptides</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term>
<term>Animals</term>
<term>Chromatography, Affinity</term>
<term>Humans</term>
<term>Mice</term>
<term>Molecular Sequence Data</term>
<term>Peptide Library</term>
<term>Transfection</term>
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<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Banque de peptides</term>
<term>Chromatographie d'affinité</term>
<term>Données de séquences moléculaires</term>
<term>Humains</term>
<term>Souris</term>
<term>Séquence d'acides aminés</term>
<term>Transfection</term>
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<front><div type="abstract" xml:lang="en">The human CXCL8 plays important roles in inflammation by activation of neutrophils through the hCXCR1 and hCXCR2 receptors. The role of hCXCR1 and hCXCR2 in the pathogenesis of inflammatory responses has encouraged the development of antagonists of these receptors. In this study, we used phage display peptide libraries to identify peptides antagonists that block the interactions between hCXCL8 and hCXCR1/2. Two linear hexapeptides (MSRAKE and CAKELR) and two disulfide-constrained hexapeptides (CLRSGRFC and CLPWKENC) were recovered by panning phage libraries on hCXCR1- and hCXCR2-transfected murine pre-B cells after specific elution with hCXCL8. Sequence analysis revealed homology between the linear hexapeptides and the N-terminal domain (1-SAKELR-6), whereas the constrained peptides are composed of non-contiguous amino acids mimicking spatial structure on the surface of folded C-terminal portion of hCXCL8 (50-CLDPKENWVQRVVEKFLKRAENS-72). The synthetic linear and structurally constrained peptides competed for (125)I-hCXCL8 binding to hCXCR1 and hCXCR2 (IC(50) comprised between 10 and 100μM). Furthermore, they inhibited the intracellular calcium flux and the migration of hCXCR1/hCXCR2 transfectants; and desensitized hCXCR1 and hCXCR2 receptors on neutrophils, reducing their chemotactic responses induced by ELR-CXC chemokines (hCXCL8, hCXCL1, hCXCL2, hCXCL3, and hCXCL5). To better characterize the residues required for hCXCL8 binding, we identified three linear peptides MLRQTR, HASILP and KKEPWI specific to hCXCL8. These peptides similarly displaced the binding of (125)I-hCXCL8 to hCXCR1 (IC(50) ranging from 8.5 to 10μM) in a dose-dependent manner, inhibited hCXCL8 induced increases in the intracellular calcium, and migration of hCXCR1- and hCXCR2-transfected cells. The identified peptides could be used as antagonists of hCXCL8-induced activities related to its interaction with hCXCR1 and hCXCR2 receptors and may help in the design of new anti-inflammatory therapeutic molecules.</div>
</front>
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<country name="Tunisie"><noRegion><name sortKey="Houimel, Mehdi" sort="Houimel, Mehdi" uniqKey="Houimel M" first="Mehdi" last="Houimel">Mehdi Houimel</name>
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