title: A dimeric peptide with erythropoiesis-stimulating activity uniquely affects erythropoietin receptor ligation and cell surface expression.
abstract: Erythropoiesis-stimulating agents (ESAs) that exert long-acting antianemia effects have been developed recently, but their mechanisms are poorly understood. Analyses reveal unique erythropoietin receptor (EPOR)-binding properties for one such ESA, the synthetic EPOR agonist peginesatide. Compared with recombinant human EPO and darbepoietin, peginesatide exhibited a slow on rate, but sustained EPOR residency and resistant displacement. In EPO-dependent human erythroid progenitor UT7epo cells, culture in peginesatide unexpectedly upmodulated endogenous cell surface EPOR levels with parallel increases in full-length EPOR-68K levels. These unique properties are suggested to contribute to the durable activity of this (and perhaps additional) dimeric peptide hematopoietic growth factor receptor agonist.
authors.affiliation: Molecular Medicine Division, Maine Medical Center Research Institute, Scarborough, ME.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Verma
authors.affiliation: Affymax, Inc., Palo Alto, CA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Green
authors.affiliation: Affymax, Inc., Palo Alto, CA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schatz
authors.affiliation: Molecular Medicine Division, Maine Medical Center Research Institute, Scarborough, ME; Department of Medicine, Tufts University Medical Center, Boston, MA. Electronic address: wojchd@mmc.org.
authors.forename: Don M
authors.initials: DM
authors.lastname: Wojchowski
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D055503:Protein Multimerization; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D010455:Peptides; D017467:Receptors, Erythropoietin; D004921:Erythropoietin