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Potent Agonists of a Hematopoietic Stem Cell Cytokine Receptor, c-Mpl

Authors

  • Dr. Anna Tarasova,

    1. CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169 (Australia)
    2. Cooperative Research Centre for Polymers, 8 Redwood Drive, Notting Hill 3168 (Australia)
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  • Prof. David N. Haylock,

    1. CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169 (Australia)
    2. Department of Anatomy and Cell Biology, Monash University, Clayton 3168 (Australia)
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  • Dr. Laurence Meagher,

    1. CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169 (Australia)
    2. Cooperative Research Centre for Polymers, 8 Redwood Drive, Notting Hill 3168 (Australia)
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  • Cheang Ly Be,

    1. CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169 (Australia)
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  • Jacinta White,

    1. CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169 (Australia)
    2. Cooperative Research Centre for Polymers, 8 Redwood Drive, Notting Hill 3168 (Australia)
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  • Prof. Susan K. Nilsson,

    1. CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169 (Australia)
    2. Department of Anatomy and Cell Biology, Monash University, Clayton 3168 (Australia)
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  • Dr. Jessica Andrade,

    1. CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169 (Australia)
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  • Kellie Cartledge,

    1. CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169 (Australia)
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  • Prof. David A. Winkler

    Corresponding author
    1. CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169 (Australia)
    2. Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville 3052 (Australia)
    3. Cooperative Research Centre for Polymers, 8 Redwood Drive, Notting Hill 3168 (Australia)
    • CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169 (Australia)
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Abstract

Several growth factors feature prominently in the control of hematopoiesis. Thrombopoietin, a class I hematopoietic cytokine, plays critical roles in regulating hematopoietic stem cell numbers and also stimulates the production and differentiation of megakaryocytes, the bone marrow cells that ultimately produce platelets. Thrombopoietin interacts with the c-Mpl cell-surface receptor. Recently, several peptide and small-molecule agonists and antagonists of c-Mpl have been reported. We conducted a bioinformatics and molecular modeling study aimed at understanding the agonist activities of peptides that bind to c-Mpl, and developed new potent peptide agonists with low nanomolar activity. These agonists also show very high activity in human CD34+ primary cell cultures, and doubled the mean blood platelet counts when injected into mice.

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