Document Detail


Increased potency of an erythropoietin peptide mimetic through covalent dimerization.
MedLine Citation:
PMID:  9359108     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
N C Wrighton; P Balasubramanian; F P Barbone; A K Kashyap; F X Farrell; L K Jolliffe; R W Barrett; W J Dower
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Nature biotechnology     Volume:  15     ISSN:  1087-0156     ISO Abbreviation:  Nat. Biotechnol.     Publication Date:  1997 Nov 
Date Detail:
Created Date:  1997-12-18     Completed Date:  1997-12-18     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  9604648     Medline TA:  Nat Biotechnol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1261-5     Citation Subset:  IM    
Affiliation:
Affymax Research Institute, Palo Alto, CA 94304, USA. nick@wrighton.com
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Dimerization
Erythropoietin / chemistry,  metabolism,  pharmacology*
Mice
Molecular Mimicry*
Molecular Sequence Data
Peptides / chemistry,  metabolism,  pharmacology*
Protein Binding
Receptors, Erythropoietin / metabolism
Chemical
Reg. No./Substance:
0/Peptides; 0/Receptors, Erythropoietin; 11096-26-7/Erythropoietin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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