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Increased potency of an erythropoietin peptide mimetic through covalent dimerization

Nature Biotechnology volume 15, pages 1261–1265 (1997)Cite this article

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 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.

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Author notes

  1. Arun K. Kashyap

    Present address: University of California at Santa Cruz, Biology/Sinsheimer Lab., Steinhart Way, Santa Cruz, CA, 95064

Authors and Affiliations

  1. Affymax Research Institute, 4001 Miranda Ave., Palo Alto, CA, 94304

    Nicholas C. Wrighton, Palaniappan Balasubramanian, Ronald W. Barrett & William J. Dower

  2. The R.W. Johnson Pharmaceutical Research Institute, 1000 Route 202, Raritan, NJ, 08869

    Francis P. Barbone, Francis X. Farrell & Linda K. Jolliffe

Authors
  1. Nicholas C. Wrighton
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  2. Palaniappan Balasubramanian
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  3. Francis P. Barbone
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  4. Arun K. Kashyap
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  5. Francis X. Farrell
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  6. Linda K. Jolliffe
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  7. Ronald W. Barrett
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  8. William J. Dower
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Wrighton, N., Balasubramanian, P., Barbone, F. et al. Increased potency of an erythropoietin peptide mimetic through covalent dimerization. Nat Biotechnol 15, 1261–1265 (1997). https://doi.org/10.1038/nbt1197-1261

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  • DOI: https://doi.org/10.1038/nbt1197-1261

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