title: 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 beta common receptor. In the present work, we have delimited tissue-protective 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.
authors.affiliation: Warren Pharmaceuticals, Ossining, NY 10562, USA. mbrines@warrenpharma.com
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.forename: Pia
authors.initials: P
authors.lastname: Villa
authors.forename: Courtenay
authors.initials: C
authors.lastname: Brines
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Massimiliano
authors.initials: M
authors.lastname: De Paola
authors.forename: Zubeyde
authors.initials: Z
authors.lastname: Erbayraktar
authors.forename: Serhat
authors.initials: S
authors.lastname: Erbayraktar
authors.forename: Bruno
authors.initials: B
authors.lastname: Sepodes
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Pietro
authors.initials: P
authors.lastname: Ghezzi
authors.forename: Michael
authors.initials: M
authors.lastname: Yamin
authors.forename: Carla C
authors.initials: CC
authors.lastname: Hand
authors.forename: Qiao-wen
authors.initials: QW
authors.lastname: Xie
authors.forename: Thomas
authors.initials: T
authors.lastname: Coleman
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
mesh_terms: D000818:Animals; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism; D004921:Erythropoietin / Q000235:genetics / Q000627:therapeutic use*; D007668:Kidney / Q000293:injuries; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010211:Papilledema / Q000188:drug therapy*; D010364:Pattern Recognition, Visual / Q000502:physiology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy*; D014945:Wound Healing / Q000235:genetics*
chemical_list: D053648:Cytokine Receptor Common beta Subunit; D010455:Peptides; D004921:Erythropoietin