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Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells.

The G protein-coupled receptor (GPCR), chemokine CXC-type receptor 4 (CXCR4), and its ligand, CXCL12, mediate the retention of polymorphonuclear neutrophils (PMNs) and hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Agents that disrupt CXCL12-mediated chemoattraction of CXCR4-exp... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America December 21, 2010, Vol.107(51), pp.22255-22259
Main Author: Tchernychev, Boris
Other Authors: Ren, Yong , Sachdev, Pallavi , Janz, Jay M , Haggis, Lynn , O'Shea, Adam , Mcbride, Ed , Looby, Richard , Deng, Qing , Mcmurry, Thomas , Kazmi, Manija A , Sakmar, Thomas P , Hunt, Stephen , Carlson, Kenneth E
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1009633108
Link: http://search.proquest.com/docview/821197544/?pq-origsite=primo
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title: Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells.
format: Article
creator:
  • Tchernychev, Boris
  • Ren, Yong
  • Sachdev, Pallavi
  • Janz, Jay M
  • Haggis, Lynn
  • O'Shea, Adam
  • Mcbride, Ed
  • Looby, Richard
  • Deng, Qing
  • Mcmurry, Thomas
  • Kazmi, Manija A
  • Sakmar, Thomas P
  • Hunt, Stephen
  • Carlson, Kenneth E
subjects:
  • Animals–Drug Effects
  • Chemotaxis–Metabolism
  • Dose-Response Relationship, Drug–Metabolism
  • Hek293 Cells–Pharmacology
  • Hematopoietic Stem Cell Mobilization–Agonists
  • Hematopoietic Stem Cells–Metabolism
  • Humans–Drug Effects
  • Leukocytes, Mononuclear–Drug Effects
  • Macaca Fascicularis–Drug Effects
  • Mice–Drug Effects
  • Mice, Inbred Balb C–Drug Effects
  • Peptides–Drug Effects
  • Receptors, Cxcr4–Drug Effects
  • Signal Transduction–Drug Effects
  • Cxcr4 Protein, Human
  • Cxcr4 Protein, Mouse
  • Peptides
  • Receptors, Cxcr4
ispartof: Proceedings of the National Academy of Sciences of the United States of America, December 21, 2010, Vol.107(51), pp.22255-22259
description: The G protein-coupled receptor (GPCR), chemokine CXC-type receptor 4 (CXCR4), and its ligand, CXCL12, mediate the retention of polymorphonuclear neutrophils (PMNs) and hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Agents that disrupt CXCL12-mediated chemoattraction of CXCR4-expressing cells mobilize PMNs and HSPCs into the peripheral circulation and are therapeutically useful for HSPC collection before autologous bone marrow transplantation (ABMT). Our aim was to develop unique CXCR4-targeted therapeutics using lipopeptide GPCR modulators called pepducins. A pepducin is a synthetic molecule composed of a peptide derived from the amino acid sequence of one of the intracellular (IC) loops of a target GPCR coupled to a lipid tether. We prepared and screened a small CXCR4-targeted pepducin library and identified several pepducins with in vitro agonist activity, including ATI-2341, whose peptide sequence derives from the first IC loop. ATI-2341 induced CXCR4and G protein-dependent signaling, receptor internalization, and chemotaxis in CXCR4-expressing cells. It also induced dose-dependent peritoneal recruitment of PMNs when administered i.p. to mice. However, when administered systemically by i.v. bolus, ATI-2341 acted as a functional antagonist and dose-dependently mediated release of PMNs from the bone marrow of both mice and cynomolgus monkeys. ATI-2341--mediated release of granulocyte/macrophage progenitor cells from the bone marrow was confirmed by colony-forming assays. We conclude that ATI-2341 is a potent and efficacious mobilizer of bone marrow PMNs and HSPCs and could represent a previously undescribed therapeutic approach for the recruitment of HSPCs before ABMT. doi/ 10.1073/pnas.1009633108
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1009633108
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleDiscovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells.
creatorTchernychev, Boris ; Ren, Yong ; Sachdev, Pallavi ; Janz, Jay M ; Haggis, Lynn ; O'Shea, Adam ; Mcbride, Ed ; Looby, Richard ; Deng, Qing ; Mcmurry, Thomas ; Kazmi, Manija A ; Sakmar, Thomas P ; Hunt, Stephen ; Carlson, Kenneth E
contributorTchernychev, Boris (correspondence author) ; Tchernychev, Boris (record owner)
ispartofProceedings of the National Academy of Sciences of the United States of America, December 21, 2010, Vol.107(51), pp.22255-22259
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1009633108
subjectAnimals–Drug Effects ; Chemotaxis–Metabolism ; Dose-Response Relationship, Drug–Metabolism ; Hek293 Cells–Pharmacology ; Hematopoietic Stem Cell Mobilization–Agonists ; Hematopoietic Stem Cells–Metabolism ; Humans–Drug Effects ; Leukocytes, Mononuclear–Drug Effects ; Macaca Fascicularis–Drug Effects ; Mice–Drug Effects ; Mice, Inbred Balb C–Drug Effects ; Peptides–Drug Effects ; Receptors, Cxcr4–Drug Effects ; Signal Transduction–Drug Effects ; Cxcr4 Protein, Human ; Cxcr4 Protein, Mouse ; Peptides ; Receptors, Cxcr4
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descriptionThe G protein-coupled receptor (GPCR), chemokine CXC-type receptor 4 (CXCR4), and its ligand, CXCL12, mediate the retention of polymorphonuclear neutrophils (PMNs) and hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Agents that disrupt CXCL12-mediated chemoattraction of CXCR4-expressing cells mobilize PMNs and HSPCs into the peripheral circulation and are therapeutically useful for HSPC collection before autologous bone marrow transplantation (ABMT). Our aim was to develop unique CXCR4-targeted therapeutics using lipopeptide GPCR modulators called pepducins. A pepducin is a synthetic molecule composed of a peptide derived from the amino acid sequence of one of the intracellular (IC) loops of a target GPCR coupled to a lipid tether. We prepared and screened a small CXCR4-targeted pepducin library and identified several pepducins with in vitro agonist activity, including ATI-2341, whose peptide sequence derives from the first IC loop. ATI-2341 induced CXCR4and G protein-dependent signaling, receptor internalization, and chemotaxis in CXCR4-expressing cells. It also induced dose-dependent peritoneal recruitment of PMNs when administered i.p. to mice. However, when administered systemically by i.v. bolus, ATI-2341 acted as a functional antagonist and dose-dependently mediated release of PMNs from the bone marrow of both mice and cynomolgus monkeys. ATI-2341--mediated release of granulocyte/macrophage progenitor cells from the bone marrow was confirmed by colony-forming assays. We conclude that ATI-2341 is a potent and efficacious mobilizer of bone marrow PMNs and HSPCs and could represent a previously undescribed therapeutic approach for the recruitment of HSPCs before ABMT. doi/ 10.1073/pnas.1009633108
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authorTchernychev, Boris ; Ren, Yong ; Sachdev, Pallavi ; Janz, Jay M ; Haggis, Lynn ; O'Shea, Adam ; Mcbride, Ed ; Looby, Richard ; Deng, Qing ; Mcmurry, Thomas ; Kazmi, Manija A ; Sakmar, Thomas P ; Hunt, Stephen ; Carlson, Kenneth E
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