Branched Peg Remodeling and Glycosylation of Glucagon-Like Peptides-1 [Glp-1]

a glycosylation and branched peg technology, applied in the field of glucagon-like peptides (glp1) and glp1 peptides, can solve the problems of limited potential therapeutic use and dire consequences for individuals and society at large, and achieve enhanced glycemic control, improved glycemic control, and controlled more or less effectively

Inactive Publication Date: 2008-12-04
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]Diabetes and disorders of glycemic control are serious conditions which, if unchecked can have dire consequences for the individual and society at large. Although type 1 diabetes can be controlled more or less effectively with insulin injections, there are multiple pathways of glycemic control.

Problems solved by technology

Diabetes and disorders of glycemic control are serious conditions which, if unchecked can have dire consequences for the individual a

Method used

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  • Branched Peg Remodeling and Glycosylation of Glucagon-Like Peptides-1 [Glp-1]
  • Branched Peg Remodeling and Glycosylation of Glucagon-Like Peptides-1 [Glp-1]
  • Branched Peg Remodeling and Glycosylation of Glucagon-Like Peptides-1 [Glp-1]

Examples

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example 1

1.1 Preparation of Glucagon-Like Peptide Mutants Comprising Artificial Glycosylation Sites

[0454]Mutations in the amino acid sequence of Glucagon-Like Peptide-1 (GLP-1) will be made in order to introduce sites for O-linked glycosylation, such that the protein may be modified at these sites using the method of the present invention. Mutatants can be created using well known methods for solid state synthesis. Alternatively, mutations will be introduced into a nucleic acid the sequence encoding GLP-1 such that O-linked glycosylation sites will be introduced at each position along the peptide back bone.

[0455]The following are some exemplary GLP-1 mutants.

GLP-1 GlycopeptidesAc-X-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2H-X-EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2HA-X-GTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2HAE-X-TFTSDVSSYLEGQAAKEFIAWLVKGR-NH2HAEG-X-FTSDVSSYLEGQAAKEFIAWLVKGR-NH2HAEGT-X-TSDVSSYLEGQAAKEFIAWLVKGR-NH2HAEGTF-X-SDVSSYLEGQAAKEFIAWLVKGR-NH2HAEGTFT-X-DVSSYLEGQAAKEFIAWLVKGR-NH2HAEGTFTS-X-VSSYLEGQAAKEFIAWLV...

example 2

Determination of Biological Activity of GLP-1 Peptides

[0477]Methods for measuring biological activity of GLP-1 are known in the art. In particular, GLP-1 activity will be measured in vivo and in vitro as disclosed in Xiao Q., et al. (2001) Biochemistry 40:2860-2869, which is incorporated herein by reference in its entirety.

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Abstract

The present invention provides polypeptides that include an O-linked glycoconjugate in which a species such as a water-soluble polymer, a therapeutic agent of a biomolecule is covalently linked through an intact O-linked glycosyl residue to the polypeptide. The polypeptides of the invention include wild-type peptides and mutant peptides that include an O-linked glycosylation site that is not present in the wild-type peptide. Also provided are methods of making the peptides of the invention and methods, pharmaceutical compositions containing the peptides and methods of treating, ameliorating or preventing diseased in mammals by administering an amount of a peptide of the invention sufficient to achieve the desired response.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]The present application is a U.S. national phase application of PCT / US2005 / 024781 filed Jul. 13, 2005 and claims priority to U.S. Provisional Patent Application No. 60 / 587,738, filed Jul. 13, 2004 and U.S. Provisional Patent Application No. 60 / 608,723 filed Sep. 10, 2004, the disclosures of which are incorporated herein by reference in their entirety for all purposes.FIELD OF THE INVENTION[0002]The present invention relates to O-linked glycosylated glycopeptides, particularly glucagon-like peptide-1 (GLP-1) and GLP-1 peptide mutants that include O-linked glycosylation sites not present in the wild-type peptide.BACKGROUND OF THE INVENTION[0003]Glucagon-like peptide-1 (GLP-1) is an important glucoincretin hormone secreted from intestinal L cells in response to nutrient ingestion. GLP-1 functions to regulate plasma glucose levels via various independent mechanisms, making it an ideal candidate for treatment of diabetes, and possibly useful ...

Claims

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Application Information

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IPC IPC(8): A61K38/22C07K14/575C07H21/00C12N1/20A61P3/10A61P3/04
CPCC07K14/605A61K38/00A61P3/00A61P3/04A61P3/08A61P3/10A61P7/12
Inventor DEFREES, SHAWN
Owner NOVO NORDISK AS
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