title: Increased potency of an erythropoietin peptide mimetic through covalent dimerization.
abstract: 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.
authors.affiliation: Affymax Research Institute, Palo Alto, CA 94304, USA. nick@wrighton.com
authors.forename: N C
authors.initials: NC
authors.lastname: Wrighton
authors.forename: P
authors.initials: P
authors.lastname: Balasubramanian
authors.forename: F P
authors.initials: FP
authors.lastname: Barbone
authors.forename: A K
authors.initials: AK
authors.lastname: Kashyap
authors.forename: F X
authors.initials: FX
authors.lastname: Farrell
authors.forename: L K
authors.initials: LK
authors.lastname: Jolliffe
authors.forename: R W
authors.initials: RW
authors.lastname: Barrett
authors.forename: W J
authors.initials: WJ
authors.lastname: Dower
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019281:Dimerization; D004921:Erythropoietin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D017467:Receptors, Erythropoietin / Q000378:metabolism
chemical_list: D010455:Peptides; D017467:Receptors, Erythropoietin; D004921:Erythropoietin