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AssigneeIndiana University Research and Technology Corporation
InventorsRichard D. Dimarchi, David l. Smiley, Maria Dimarchi, Joseph Chabenne, Jonathan Day, James Patterson, Brian Ward
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Modified glucagon peptides are disclosed having enhanced potency at the glucagon receptor relative to native glucagon. Further modification of the glucagon peptides by forming intramolecular bridges or the substitution of the terminal carboxylic acid with an amide group produces peptides exhibiting glucagon/GLP-1 receptor co-agonist activity. The solubility and stability of these high potency glucagon analogs can be further improved by modification of the polypeptides by pegylation, acylation, alkylation, substitution of carboxy terminal amino acids, C-terminal truncation, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 26 (GPSSGAPPPS), SEQ ID NO: 27 (KRNRNNIA) and SEQ ID NO: 28 (KRNR).
A glucagon peptide comprising the amino acid sequence of SEQ ID NO:
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The glucagon peptide of claim 1 or 82, further comprising one or more modifications selected from the group consisting of:
The glucagon peptide of claim 1 or 82, comprising a C-terminal amide.
The glucagon peptide of claim 1 or 82, comprising an amino acid substitution at position 1, position 2, or positions 1 and 2, wherein the amino acid substitution(s) achieve DPP-IV protease resistance.
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A non-native glucagon peptide modified to comprise an acyl group or alkyl group covalently linked to the amino acid at position 10 of the glucagon peptide.
10-65. (canceled)
The glucagon peptide of claim 1 or 88, wherein the amino acid at position 10 of the glucagon peptide is an amino acid of Formula I, Formula II, or Formula III.
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The glucagon peptide of claim 1 or 88, further comprising a spacer between the amino acid at position 10 of the glucagon peptide and the acyl group or alkyl group.
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72-81. (canceled)
A non-native glucagon peptide that differs from SEQ ID NO:
83-87. (canceled)
89-108. (canceled)
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Dependencies are inferred from the claim text.