Small peptides as potent mimetics of the protein hormone erythropoietin.
Random phage display peptide libraries and affinity selective methods were used to isolate small peptides that bind to and activate the receptor for the cytokine erythropoietin (EPO). In a panel of in vitro biological assays, the peptides act as full agonists and they can also stimulate erythropoiesis in mice. These agonists are represented by a 14- amino acid disulfide-bonded, cyclic peptide with the minimum consensus sequence YXCXXGPXTWXCXP, where X represents positions allowing occupation by several amino acids. The amino acid sequences of these peptides are not found in the primary sequence of EPO. The signaling pathways activated by these peptides appear to be identical to those induced by the natural ligand. This discovery may form the basis for the design of small molecule mimetics of EPO.
Wrighton
N C
NC
Affymax Research Institute, 4001 Miranda Avenue, Palo Alto, CA 94304, USA.
Farrell
F X
FX
Chang
R
R
Kashyap
A K
AK
Barbone
F P
FP
Mulcahy
L S
LS
Johnson
D L
DL
Barrett
R W
RW
Jolliffe
L K
LK
Dower
W J
WJ
D000595:Amino Acid Sequence; D000818:Animals; D001435:Bacteriophages; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003001:Cloning, Molecular; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D017467:Receptors, Erythropoietin / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility; D014443:Tyrosine / Q000378:metabolism
C099963:EPO mimetic peptide 1; D008024:Ligands; D010456:Peptides, Cyclic; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin; D014443:Tyrosine