Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin.
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.
Brines
Michael
M
Warren Pharmaceuticals, Ossining, NY 10562, USA. mbrines@warrenpharma.com
Patel
Nimesh S A
NS
Villa
Pia
P
Brines
Courtenay
C
Mennini
Tiziana
T
De Paola
Massimiliano
M
Erbayraktar
Zubeyde
Z
Erbayraktar
Serhat
S
Sepodes
Bruno
B
Thiemermann
Christoph
C
Ghezzi
Pietro
P
Yamin
Michael
M
Hand
Carla C
CC
Xie
Qiao-wen
QW
Coleman
Thomas
T
Cerami
Anthony
A
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*
D053648:Cytokine Receptor Common beta Subunit; D010455:Peptides; D004921:Erythropoietin