Synthetic erythropoietic proteins: tuning biological performance by site-specific polymer attachment

Chem Biol. 2005 Mar;12(3):371-83. doi: 10.1016/j.chembiol.2005.01.017.

Abstract

Chemical synthesis in combination with precision polymer modification allows the systematic exploration of the effect of protein properties, such as charge and hydrodynamic radius, on potency using defined, homogeneous conjugates. A series of polymer-modified synthetic erythropoiesis proteins were constructed that had a polypeptide chain similar to the amino acid sequence of human erythropoietin but differed significantly in the number and type of attached polymers. The analogs differed in charge from +5 to -26 at neutral pH and varied in molecular weight from 30 to 54 kDa. All were active in an in vitro cell proliferation assay. However, in vivo potency was found to be strongly dependent on overall charge and size. The trends observed in this study may serve as starting points for the construction of more potent synthetic EPO analogs in the future.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Erythropoiesis / physiology*
  • Erythropoietin / chemical synthesis
  • Erythropoietin / metabolism
  • Erythropoietin / physiology
  • Humans
  • Macaca fascicularis
  • Mice
  • Molecular Sequence Data
  • Polymers / chemical synthesis*
  • Polymers / metabolism
  • Polymers / pharmacology
  • Proteins / chemical synthesis*
  • Proteins / metabolism
  • Proteins / physiology
  • Rats

Substances

  • Polymers
  • Proteins
  • Erythropoietin