Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells
| Autor: | Richard J. Looby, Thomas J. McMurry, Manija A. Kazmi, Kenneth E. Carlson, Lynn Haggis, Jay M. Janz, Adam O'Shea, Stephen W. Hunt, Ed McBride, Pallavi Sachdev, Yong Ren, Boris Tchernychev, Thomas P. Sakmar, Qing Deng |
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| Rok vydání: | 2010 |
| Předmět: |
Receptors
CXCR4 Chemokine Granulocyte CXCR4 Mice medicine Animals Humans Progenitor cell Pepducin Hematopoietic Stem Cell Mobilization Mice Inbred BALB C Multidisciplinary Dose-Response Relationship Drug biology Chemotaxis Biological Sciences Hematopoietic Stem Cells Macaca fascicularis Haematopoiesis HEK293 Cells medicine.anatomical_structure Immunology Leukocytes Mononuclear Cancer research biology.protein Bone marrow Peptides Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 107:22255-22259 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1009633108 |
| Popis: | 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 CXCR4- and 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. |
| Databáze: | OpenAIRE |
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