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

journal contribution
posted on 2023-06-08, 13:26 authored by Michael Brines, Nimesh S A Patel, Pia Villa, Courtenay Brines, Tiziana Mennini, Massimiliano De Paola, Zubeyde Erbayraktar, Serhat Erbayraktar, Bruno Sepodes, Christoph Thiemermann, Pietro Ghezzi, Michael Yamin, Carla C Hand, Qiao-wen Xie, Thomas Coleman, Anthony Cerami
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.

History

Publication status

  • Published

Journal

Proceedings of the National Academy of Sciences

ISSN

1091-6490

Publisher

National Academy of Sciences

Issue

31

Volume

105

Page range

10925-10930

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-11-02

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