Peptide dimers as agonists of the erythropoietin (EPO) receptor, and associated methods of synthesis and use
First Claim
1. A method for synthesizing a peptide dimer, comprising:
- (a) providing first and second peptide chains linked to a linking moiety LK, said chains each possessing multiple amino acid residues capable of disulfide bond formation upon oxidation; and
(b) oxidizing in a single oxidation step said peptide chains in a manner effective to preferentially promote formation of disulfide bonds between residues in the same peptide chain relative to formation of disulfide bonds in different peptide chains, and wherein at least 50% of said peptide dimer comprises a peptide chain having an intrapeptide disulfide bond.
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Abstract
Novel peptide dimers are provided that bind and activate the erythropoietin receptor (EPO-R) or otherwise act as an EPO agonist. The novel compounds have a first peptide chain R1 and a second peptide chain R2, wherein R1 and R2 may be the same or different, and are linked through a linking moiety. R1 is approximately 10 to 40 amino acid residues in length and comprises the sequence X3X4X5GPX6TX7X8X9 (SEQ ID NO: 1) wherein X3 is C or Hoc, X4 is R, H, L or W, X5 is M, F, I or nor-leucine (J), X6 is any one of the 20 genetically coded L-amino acids or J, X7 is W, 1-naphthylalanine (B) or 2-naphthylalanine (U), X8 is D, E, I, L or V, and X9 is C or Hoc. Similarly, R2 comprises the sequence X′3X′4X′5GPX′6TX′7X′8X′9 (SEQ IN NO: 2) wherein X′3 is C or Hoc, X′4 is R, H, L or W, X′5 is M, F, I or J, X′6 is any one of the 20 genetically coded L-amino acids or J, X′7 is W, B or U, X8′ is D, E, I, L or V, and X′9 is C or Hoc. Methods for synthesizing the compounds are provided as well, as are pharmaceutical compositions and methods of use.
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Citations
13 Claims
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1. A method for synthesizing a peptide dimer, comprising:
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(a) providing first and second peptide chains linked to a linking moiety LK, said chains each possessing multiple amino acid residues capable of disulfide bond formation upon oxidation; and (b) oxidizing in a single oxidation step said peptide chains in a manner effective to preferentially promote formation of disulfide bonds between residues in the same peptide chain relative to formation of disulfide bonds in different peptide chains, and wherein at least 50% of said peptide dimer comprises a peptide chain having an intrapeptide disulfide bond. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
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Specification