Identification of biologically active peptides that inhibit binding of human CXCL8 to its receptors from a random phage-epitope library.
Identifieur interne : 000068 ( Main/Exploration ); précédent : 000067; suivant : 000069Identification of biologically active peptides that inhibit binding of human CXCL8 to its receptors from a random phage-epitope library.
Auteurs : Mehdi Houimel [Tunisie] ; Luca MazzucchelliSource :
- Journal of leukocyte biology [ 1938-3673 ] ; 2009.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Anticorps monoclonaux (MeSH), Banque de peptides (MeSH), Cartographie épitopique (MeSH), Chimiotaxie des leucocytes (MeSH), Granulocytes neutrophiles (MeSH), Humains (MeSH), Inflammation (immunologie), Interleukine-8 (métabolisme), Lapins (MeSH), Liaison aux protéines (effets des médicaments et des substances chimiques), Peptides (immunologie), Récepteurs à l'interleukine-8 (métabolisme), Épitopes (immunologie).
- MESH :
- effets des médicaments et des substances chimiques : Liaison aux protéines.
- immunologie : Inflammation, Peptides, Épitopes.
- métabolisme : Interleukine-8, Récepteurs à l'interleukine-8.
- Animaux, Anticorps monoclonaux, Banque de peptides, Cartographie épitopique, Chimiotaxie des leucocytes, Granulocytes neutrophiles, Humains, Lapins.
English descriptors
- KwdEn :
- Animals (MeSH), Antibodies, Monoclonal (MeSH), Chemotaxis, Leukocyte (MeSH), Epitope Mapping (MeSH), Epitopes (immunology), Humans (MeSH), Inflammation (immunology), Interleukin-8 (metabolism), Neutrophils (MeSH), Peptide Library (MeSH), Peptides (immunology), Protein Binding (drug effects), Rabbits (MeSH), Receptors, Interleukin-8 (metabolism).
- MESH :
- chemical , immunology : Epitopes, Peptides.
- chemical , metabolism : Interleukin-8, Receptors, Interleukin-8.
- chemical : Antibodies, Monoclonal, Peptide Library.
- drug effects : Protein Binding.
- immunology : Inflammation.
- Animals, Chemotaxis, Leukocyte, Epitope Mapping, Humans, Neutrophils, Rabbits.
Abstract
A random bacteriophage peptide library was used to map structural features of human (h)CXCR1 and hCXCR2 by determining the epitopes of neutralizing mAb 5A12 anti-hCXCR1 and mAb 6C6 anti-hCXCR2. After three rounds of biopanning, five mAb5 A12- and four mAb 6C6-binding peptides were identified from a 6-mer peptide library. Consensus sequences (S/T)(1)(F/A/N/D)(2)(I/M)(3)W(4)D(5)F(6) and F/L/M)(1)W(2)(D/N/L)(3)D(4)F(5)W(6) were deduced from sequences of these peptides. They correspond to a highly conserved N-domain sequence (9)MWDF(12) of hCXCR1 and (13)DFW(15) of hCXCR2. The phage bearing the peptides showed specific binding to immobilized mAb 5A12 or mAb 6CC, and over 86% of phages bound were competitively inhibited by free synthetic peptides. In FACScan analysis, all selected phage peptides were able to strongly inhibit the binding of mAb 5A12 and mAb 6C6 to hCXCR1- and hCXCR2-transfected preB 300-19 murine cells. Furthermore, synthetic peptides of the corresponding phage epitopes were effective in blocking the antibody-CXCR1/2 interactions and to inhibit the binding of hCXCL8 to hCXCR1 and hCXCR2 transfectants. Peptides 5A12/2 (SAMWDF) and 6C6/1 (FWDDFW) competed effectively for (125)I-hCXCL8 binding to hCXCR1 and hCXCR2 with IC(50), respectively, equal to 10 muM and 5.4 muM. Calcium release and chemotaxis of hCXCR1/2 transfectants or human neutrophils were inhibited by all peptides in a dose-dependent manner. Furthermore, the peptide 6C6/1 FWDDFW showed inhibitory effects on chemotaxis of human netrophils induced by hCXCR2 chemokines such as hCXCL1-3 and hCXCL5. Specificities of peptides 5A12/2 and 6C6/1 were assessed with hCXCR3, hCXCR4, hCXCR5, hCCR3, and hCCR5 receptors. In vivo, peptides 5A12/2 and p6C6/1 blockade hCXCL8-induced neutrophil recruitment in skin inflammation in rabbits. Taken together, these data demonstrate that phage-display analysis provides information about the relative location of amino acids on the N-domain surfaces of hCXCR1 and hCXCR2 proteins using antibody imprints of the receptor-surface structure. The derived mimotopes could be used as inhibitors of hCXCL8-induced activities related to its interaction with the N-domain of hCXCR1 and hCXCR2.
DOI: 10.1189/jlb.0608380
PubMed: 19118103
Affiliations:
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Le document en format XML
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<series><title level="j">Journal of leukocyte biology</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term>
<term>Antibodies, Monoclonal (MeSH)</term>
<term>Chemotaxis, Leukocyte (MeSH)</term>
<term>Epitope Mapping (MeSH)</term>
<term>Epitopes (immunology)</term>
<term>Humans (MeSH)</term>
<term>Inflammation (immunology)</term>
<term>Interleukin-8 (metabolism)</term>
<term>Neutrophils (MeSH)</term>
<term>Peptide Library (MeSH)</term>
<term>Peptides (immunology)</term>
<term>Protein Binding (drug effects)</term>
<term>Rabbits (MeSH)</term>
<term>Receptors, Interleukin-8 (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Anticorps monoclonaux (MeSH)</term>
<term>Banque de peptides (MeSH)</term>
<term>Cartographie épitopique (MeSH)</term>
<term>Chimiotaxie des leucocytes (MeSH)</term>
<term>Granulocytes neutrophiles (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Inflammation (immunologie)</term>
<term>Interleukine-8 (métabolisme)</term>
<term>Lapins (MeSH)</term>
<term>Liaison aux protéines (effets des médicaments et des substances chimiques)</term>
<term>Peptides (immunologie)</term>
<term>Récepteurs à l'interleukine-8 (métabolisme)</term>
<term>Épitopes (immunologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Epitopes</term>
<term>Peptides</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Interleukin-8</term>
<term>Receptors, Interleukin-8</term>
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<term>Peptide Library</term>
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<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Protein Binding</term>
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<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Liaison aux protéines</term>
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<term>Peptides</term>
<term>Épitopes</term>
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<term>Anticorps monoclonaux</term>
<term>Banque de peptides</term>
<term>Cartographie épitopique</term>
<term>Chimiotaxie des leucocytes</term>
<term>Granulocytes neutrophiles</term>
<term>Humains</term>
<term>Lapins</term>
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<front><div type="abstract" xml:lang="en">A random bacteriophage peptide library was used to map structural features of human (h)CXCR1 and hCXCR2 by determining the epitopes of neutralizing mAb 5A12 anti-hCXCR1 and mAb 6C6 anti-hCXCR2. After three rounds of biopanning, five mAb5 A12- and four mAb 6C6-binding peptides were identified from a 6-mer peptide library. Consensus sequences (S/T)(1)(F/A/N/D)(2)(I/M)(3)W(4)D(5)F(6) and F/L/M)(1)W(2)(D/N/L)(3)D(4)F(5)W(6) were deduced from sequences of these peptides. They correspond to a highly conserved N-domain sequence (9)MWDF(12) of hCXCR1 and (13)DFW(15) of hCXCR2. The phage bearing the peptides showed specific binding to immobilized mAb 5A12 or mAb 6CC, and over 86% of phages bound were competitively inhibited by free synthetic peptides. In FACScan analysis, all selected phage peptides were able to strongly inhibit the binding of mAb 5A12 and mAb 6C6 to hCXCR1- and hCXCR2-transfected preB 300-19 murine cells. Furthermore, synthetic peptides of the corresponding phage epitopes were effective in blocking the antibody-CXCR1/2 interactions and to inhibit the binding of hCXCL8 to hCXCR1 and hCXCR2 transfectants. Peptides 5A12/2 (SAMWDF) and 6C6/1 (FWDDFW) competed effectively for (125)I-hCXCL8 binding to hCXCR1 and hCXCR2 with IC(50), respectively, equal to 10 muM and 5.4 muM. Calcium release and chemotaxis of hCXCR1/2 transfectants or human neutrophils were inhibited by all peptides in a dose-dependent manner. Furthermore, the peptide 6C6/1 FWDDFW showed inhibitory effects on chemotaxis of human netrophils induced by hCXCR2 chemokines such as hCXCL1-3 and hCXCL5. Specificities of peptides 5A12/2 and 6C6/1 were assessed with hCXCR3, hCXCR4, hCXCR5, hCCR3, and hCCR5 receptors. In vivo, peptides 5A12/2 and p6C6/1 blockade hCXCL8-induced neutrophil recruitment in skin inflammation in rabbits. Taken together, these data demonstrate that phage-display analysis provides information about the relative location of amino acids on the N-domain surfaces of hCXCR1 and hCXCR2 proteins using antibody imprints of the receptor-surface structure. The derived mimotopes could be used as inhibitors of hCXCL8-induced activities related to its interaction with the N-domain of hCXCR1 and hCXCR2.</div>
</front>
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