title: Potent agonists of a hematopoietic stem cell cytokine receptor, c-Mpl.
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.
authors.affiliation: CSIRO Materials Science & Engineering, Bag 10, Clayton South MDC 3169, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Tarasova
authors.forename: David N
authors.initials: DN
authors.lastname: Haylock
authors.forename: Laurence
authors.initials: L
authors.lastname: Meagher
authors.forename: Cheang Ly
authors.initials: CL
authors.lastname: Be
authors.forename: Jacinta
authors.initials: J
authors.lastname: White
authors.forename: Susan K
authors.initials: SK
authors.lastname: Nilsson
authors.forename: Jessica
authors.initials: J
authors.lastname: Andrade
authors.forename: Kellie
authors.initials: K
authors.lastname: Cartledge
authors.forename: David A
authors.initials: DA
authors.lastname: Winkler
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D018360:Crystallography, X-Ray; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008533:Megakaryocytes / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D018952:Antigens, CD34; D009842:Oligopeptides; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human