Increased potency of an erythropoietin peptide mimetic through covalent dimerization

Nat Biotechnol. 1997 Nov;15(12):1261-5. doi: 10.1038/nbt1197-1261.


We have synthesized a chemically defined, dimeric form of an erythropoietin mimetic peptide (EMP) that displays 100-fold increased affinity for the erythropoietin receptor (EPOR) and correspondingly elevated potency in cell-based assays and in mice. The dimeric EMP1 was synthesized using a C-terminal lysine residue as a branch point. A beta-alanine residue was coupled to the main-chain (alpha) amino group of the lysine residue in order to provide a pseudosymmetrical scaffold where both the side-chain and main-chain were of approximately equal length. Using an orthogonal protection system, independently disulphide-cylized EMP1 moieties were synthesized upon this scaffold. The proposed mechanism of increased potency of the dimer over the parental compound EMP1 is consistent with the structure of a cocrystal of EMP1 and the extracellular domain of the EPOR in which a noncovalent peptide dimer is seen spanning the cleft between two molecules of the EPOR extracellular domain.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Dimerization
  • Erythropoietin / chemistry
  • Erythropoietin / metabolism
  • Erythropoietin / pharmacology*
  • Mice
  • Molecular Mimicry*
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Protein Binding
  • Receptors, Erythropoietin / metabolism


  • Peptides
  • Receptors, Erythropoietin
  • Erythropoietin