Alpha/beta-polypeptide analogs of glucagon-like peptide 1
AssigneesWisconsin Alumni Research Foundation, President and Fellows of Harvard College
InventorsSamuel H. Gellman, Lisa M. Johnson, Alan Attie, Mark P. Keller, Alan Saghatelian
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Abstract
Described herein are peptide analogs of glucagon-like peptide 1 (GLP-1) that retain agonist activity, but are more resistant to proteolytic degradation than native GLP-1. In the analogs, at least one α-amino acid found in the native GLP-1 is replaced with a β-amino acid residue, which may or may not be cyclically constrained. Pharmaceutical compositions containing the analogs are described, as are methods to treat diabetes, and methods to make proteolytically resistant GLP-1 analogs.
Claims25
A composition of matter comprising an isolated, unnatural analog of glucagon-like peptide 1 (GLP-1) having an N-terminus, wherein at least one α-amino acid residue in the GLP-1 located at least 12 residues from the N-terminus of the GLP-1 is replaced with a β-amino acid residue.
A synthetic, unnatural polypeptide selected from the group consisting of H-H-X-EGTFT-X-D-X-S-X-YLE-X-QAA-X-EFI-X-WLV-X-GRG-NH2 (SEQ. ID. NO:
- 16), wherein each “X,” which may be the same or different, is a β-amino acid residue.
A method to fabricate glucagon-like peptide-1 receptor agonists that are resistant to proteolytic degradation, the method comprising:
- constructing an isolated, unnatural glucagon-like peptide 1 (GLP-1) analog having an amino acid sequence identical to a native GLP-1 sequence, but replacing at least one α-amino acid residue in the native GLP-1 sequence with a β-amino acid residue, wherein the replacement β-amino acid residue is located at least 12 residues from the N-terminus of the GLP-1 analog.
Dependencies are inferred from the claim text.