A dimeric peptide with erythropoiesis stimulating activity uniquely affects erythropoietin receptor ligation and cell surface expression

• Published in: Experimental hematology Vol. 44; no. 8; pp. 765 - 769.e1
• Main Authors: Verma, Rakesh, Green, Jennifer M, Schatz, Peter J, Wojchowski, Don M
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2016
• Subjects: Advanced Basic Science; Cell Line; Cell Membrane - metabolism; Erythropoiesis - drug effects; Erythropoietin - chemistry; Erythropoietin - metabolism; Erythropoietin - pharmacology; Hematology, Oncology and Palliative Medicine; Humans; Kinetics; Peptides - chemistry; Peptides - metabolism; Peptides - pharmacology; Protein Binding; Protein Multimerization; Receptors, Erythropoietin - genetics; Receptors, Erythropoietin - metabolism; Signal Transduction
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2016.04.015

Abstract Erythropoiesis stimulating agents (ESAs) recently have been developed that exert long acting anti-anemia effects, but via poorly understood mechanisms. For one such ESA, peginesatide, analyses reveal unique EPOR binding properties for this synthetic EPOR agonist. As compared to rHu-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 also unexpectedly up-modulated endogenous cell surface EPOR levels with parallel apparent relative 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 agonists.