GIP receptor-active glucagon compounds

摘要

Glucagon peptides with increased GIP activity are provided, optionally with GLP-I and/or glucagon activity. In some embodiments, C-terminally extended glucagon peptides comprising an amino acid sequence substantially similar to native glucagon are provided herein.

主权项

1. A peptide comprising (A) the amino acid sequence of SEQ ID NO: 1 with the following amino acid modifications and (B) the amino acid sequence of GPSSGAPPPS (SEQ ID NO: 26) C-terminal to the amino acid at position 29 of SEQ ID NO: 1,
wherein the amino acid at position 2 is an selected from the group consisting of: D-serine, alanine, D-alanine, valine, glycine, N-methyl serine, N-methyl alanine, and amino isobutyric acid (AIB), wherein the amino acid at position 16 is Glu, the amino acid at position 17 is Gln, the amino acid at position 18 is Ala, the amino acid at position 20 is Lys, the amino acid at position 21 is Glu, the amino acid at position 23 is Ile, the amino acid at position 24 is Ala, and the amino acid at position 29 is a small aliphatic amino acid, wherein:
(a) the peptide further comprises at position 40 an amino acid comprising an acyl or alkyl group, which is non-native to a naturally-occurring amino acid,(b) the peptide comprises an amino acid comprising an acyl or alkyl group, which is non-native to a naturally-occurring amino acid, at position 10 of the peptide, or(c) a combination of (a) and (b); wherein, when the peptide lacks a hydrophilic moiety, the peptide exhibits at least 10% activity of native GIP at the GIP receptor, wherein the GIP potency of the peptide is within about 100-fold of GLP-1 potency of the peptide.