Journal Article

Increased potency of an erythropoietin peptide mimetic through covalent dimerization

Balasubramanian, Palaniappan, Barrett, Ronald W., Farrell, Francis X., Jolliffe, Linda K., Wrighton, Nicholas C., Barbone, Francis P., Kashyap, Arun K., Dower, William J.

1997

Overview

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 β-alanine residue was coupled to the main-chain (α) 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.

• Publisher: Nature Publishing Group US,Nature
• Subject: Agriculture / Amino Acid Sequence / Animals / Bioinformatics / Biological and medical sciences / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Dimerization / Erythropoietin - chemistry / Erythropoietin - metabolism / Erythropoietin - pharmacology / Fundamental and applied biological sciences. Psychology / Life Sciences / Methods. Procedures. Technologies / Mice / Molecular Mimicry / Molecular Sequence Data / Peptides - chemistry / Peptides - metabolism / Peptides - pharmacology / Protein Binding / Protein engineering / Receptors, Erythropoietin - metabolism / research-article