Peptide Agonist of the Thrombopoietin Receptor as Potent as the Natural Cytokine
| Autor: | Steven E. Cwirla, Palaniappan Balasubramanian, Ronald W. Barrett, Nicholas C. Wrighton, Peter J. Schatz, Wagstrom Christopher R, Duffin David J, David P. Baccanari, Robert L. Tansik, Sara C. Singer, Ann M. Davis, Chris M. Boytos, Christian M. Gates, William J. Dower, Larry C. Mattheakis |
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| Rok vydání: | 1997 |
| Předmět: |
Blood Platelets
Molecular Sequence Data Peptide Transfection Binding Competitive Cell Line Mice Megakaryocyte Peptide Library Proto-Oncogene Proteins Consensus Sequence medicine Animals Humans Amino Acid Sequence Receptors Cytokine Peptide library Receptor Erythropoietin Peptide sequence Cells Cultured Thrombopoietin chemistry.chemical_classification Thrombopoietin receptor Multidisciplinary Platelet Count Ligand (biochemistry) Recombinant Proteins Hematopoiesis Neoplasm Proteins medicine.anatomical_structure chemistry Biochemistry Peptides Dimerization Megakaryocytes Oligopeptides Receptors Thrombopoietin Cell Division |
| Zdroj: | Science. 276:1696-1699 |
| ISSN: | 1095-9203 0036-8075 |
| DOI: | 10.1126/science.276.5319.1696 |
| Popis: | Two families of small peptides that bind to the human thrombopoietin receptor and compete with the binding of the natural ligand thrombopoietin (TPO) were identified from recombinant peptide libraries. The sequences of these peptides were not found in the primary sequence of TPO. Screening libraries of variants of one of these families under affinity-selective conditions yielded a 14–amino acid peptide (Ile-Glu-Gly-Pro-Thr-Leu-Arg-Gln-Trp-Leu-Ala-Ala-Arg-Ala) with high affinity (dissociation constant ≈ 2 nanomolar) that stimulates the proliferation of a TPO-responsive Ba/F3 cell line with a median effective concentration (EC 50 ) of 400 nanomolar. Dimerization of this peptide by a carboxyl-terminal linkage to a lysine branch produced a compound with an EC 50 of 100 picomolar, which was equipotent to the 332–amino acid natural cytokine in cell-based assays. The peptide dimer also stimulated the in vitro proliferation and maturation of megakaryocytes from human bone marrow cells and promoted an increase in platelet count when administered to normal mice. |
| Databáze: | OpenAIRE |
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