Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin.
Many disease processes activate a cellular stress response that initiates a cascade of inflammation and damage. However, this process also triggers a tissue protection and repair system mediated by locally-produced hyposialated erythropoietin (hsEPO). Although recombinant EPO is used widely for treating anemia, potential use of recombinant EPO for tissue-protection is limited by rises in hematocrit, platelet activation, and selectin expression resulting in a high risk of thrombosis. Importantly, the erythropoietic and tissue-protective effects of EPO are mediated by different receptors. Whereas EPO stimulates red cell progenitors by binding to an EPO receptor (EPOR) homodimer, a heterodimer receptor complex composed of EPOR and β common receptor (βcR) subunits, termed the innate repair receptor (IRR), activates tissue protection and repair. The IRR is typically not expressed by normal tissues, but instead is rapidly induced by injury or inflammation. Based on this understanding, EPO derivatives have been developed which selectively activate the IRR without interacting with the EPOR homodimer. The latest generation of specific ligands of the IRR includes an 11 amino acid peptide modeled from the three dimensional structure of the EPO in the region of helix B called pyroglutamate helix B surface peptide (pHBSP; ARA-290). Despite a short plasma half-life (~2min), pHBSP activates a molecular switch that triggers sustained biological effects that have been observed in a number of experimental animal models of disease and in clinical trials. This review summarizes pharmacokinetic and pharmacodynamic data and discusses the molecular mechanisms underlying the long-lasting effects of this short-lived peptide.
Department of Drug Science and Technology, University of Turin, Turin, Italy. Electronic address: massimo.collino@unito.it.
Massimo
M
Collino
Queen Mary University of London, Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Christoph
C
Thiemermann
Araim Pharmaceuticals, Tarrytown, NY, USA.
Anthony
A
Cerami
Araim Pharmaceuticals, Tarrytown, NY, USA.
Michael
M
Brines
D000818:Animals; D004921:Erythropoietin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020033:Protein Isoforms / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D017467:Receptors, Erythropoietin / Q000378:metabolism
D009842:Oligopeptides; D020011:Protective Agents; D020033:Protein Isoforms; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; C576178:cibinetide
ARA 290; Erythropoietin; Innate repair receptor; Pyroglutamate helix B surface protein; β common receptor