Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin

Abstract

Erythropoietin (EPO), a member of the type 1 cytokine superfamily, plays a critical hormonal role regulating erythrocyte production as well as a paracrine/autocrine role in which locally produced EPO protects a wide variety of tissues from diverse injuries. Significantly, these functions are mediated by distinct receptors: hematopoiesis via the EPO receptor homodimer and tissue protection via a heterocomplex composed of the EPO receptor and CD131, the ␤ common receptor. In the present work, we have delimited tissueprotective domains within EPO to short peptide sequences. We demonstrate that helix B (amino acid residues 58 -82) of EPO, which faces the aqueous medium when EPO is bound to the receptor homodimer, is both neuroprotective in vitro and tissue protective in vivo in a variety of models, including ischemic stroke, diabetes-induced retinal edema, and peripheral nerve trauma. Remarkably, an 11-aa peptide composed of adjacent amino acids forming the aqueous face of helix B is also tissue protective, as confirmed by its therapeutic benefit in models of ischemic stroke and renal ischemia-reperfusion. Further, this peptide simulating the aqueous surface of helix B also exhibits EPO's trophic effects by accelerating wound healing and augmenting cognitive function in rodents. As anticipated, neither helix B nor the 11-aa peptide is erythropoietic in vitro or in vivo. Thus, the tissue-protective activities of EPO are mimicked by small, nonerythropoietic peptides that simulate a portion of EPO's three-dimensional structure.cognition ͉ cytoprotection ͉ excitotoxicity ͉ ischemia-reperfusion injury ͉ wound healing

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

“…100 Beneficial effects of both EPO and its nonhematopoietic derivatives and mimetics have been described in models of peripheral axonal nerve injury, injury-induced Wallerian degeneration, diabetic, and HIV-associated neuropathy. 41,[101][102][103][104][105] In these conditions, the anti-cytokine, antiapoptotic, anti-oxidative, and trophic effects on both neurons and oligodendrocyte progenitor cells are likely to reduce inflammation and preserve myelination and neuronal function. 33,67,[91][92][93][94][95][96][97][98]102,103 The initial observation by Grimm et al 106 of a potent neuroprotective effect of EPO in light-induced retinal degeneration has been confirmed in many other models of retinal disease in which EPO derivatives are in consideration for clinical use.…”

Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns

“…In addition, the thrombocytes stimulated are highly reactive (12) and can interact with activated endothelial cells, resulting in thrombosis. Therefore, several nonerythropoietic EPO derivatives have been developed, most recently an 11 amino acid peptide known as ARA290 that mimics a portion of helix B of the EPO molecule (13,14). ARA290 selectively binds the heteromeric receptor composed of the EPO receptor (EPO-R) and the β-common receptor (CD131), which is responsible for the tissue-protective effects of EPO and does not interact with the erythropoietic EPO-R homodimer.…”

Topological transformation of liposomes by a membrane-affecting domain of recombinant human erythropoietin

“…For a long time, the biological function of this helix was unexplained. Just recently, it was identified to be involved in the neuroprotective signal transduction (Arcasoy, 2008;Brines et al, 2008). If, and in which form, this membraneaffecting property is of biological relevance is one of the exciting questions for future studies.…”

“…The erythropoietic effect of rh-Epo results from binding, reorientation, and activation of the Epo-receptor homodimer (Epo-R 2 ) (Fisher, 2003;Matthews et al, 1996;Seubert et al, 2003;Tilbrook and Klinken, 1999). Since the approval of rh-Epo in patients with chronic renal failure, a wide range of pleiotropic properties of rh-Epo, such as neuroprotective properties in ischemia and spinal cord injury, stimulation of angiogenesis and macrophages, as well as cardiovascular protective functions, have been investigated (Arcasoy, 2008;Brines et al, 2008;Fisher, 2003;Haroon et al, 2003;Jelkmann, 2005Jelkmann, , 2007Lykissas et al, 2007;Smith et al, 2003). Modification of the rh-Epo molecule through carbamylation inhibits the erythropoietic function but retains its neuroprotective activity.…”