Contribution of site-specific PEGylation to the dipeptidyl peptidase IV stability of glucose-dependent insulinotropic polypeptide

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 18; pp. 4114 - 4117
• Main Authors: Salhanick, Arthur I., Clairmont, Kevin B., Buckholz, Thomas M., Pellegrino, Carla M., Ha, Sha, Lumb, Kevin J.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-09-2005; Elsevier
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; CHO Cells; Cricetinae; Cyclic AMP - metabolism; Dipeptidyl Peptidase 4 - chemistry; Dipeptidyl Peptidase 4 - metabolism; DPPIV; Enzyme Stability; General and cellular metabolism. Vitamins; GIP; Glucose - metabolism; Glucose - pharmacology; Insulin - metabolism; Medical sciences; Molecular Sequence Data; PEGylation; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Pharmacology. Drug treatments; Polyethylene Glycols - chemistry; DPPIV; PEGylation; GIP; Dipeptidyl-peptidase IV; Agonist; Stability; Peptides; Enzyme; Biological activity; Ethylene oxide polymer; Site specificity; C terminal-Sequence; Peptidases; Hydrolysis resistance; Chemical modification; N terminal-Sequence; Hydrolases; Gastric inhibitory peptide; Biological receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.06.002

Potent and DPPIV-stable PEGylated GIP peptides are reported.
The effects of PEGylation of glucose-dependent insulinotropic polypeptide (GIP) on potency and dipeptidyl peptidase IV (DPPIV) stability are reported. N-terminal modification of GIP(1–30) with 40
kDa polyethylene glycol (PEG) abrogates functional activity. In contrast, C-terminal PEGylation of GIP(1–30) maintains full agonism and reasonable potency at the GIP receptor and confers a high level of DPPIV resistance. Moreover, the dual modification of N-terminal palmitoylation and C-terminal PEGylation results in a full agonist of comparable potency to native GIP that is stable to DPPIV cleavage. The results provide the basis for the development of long acting, PEGylated GIP, GIP variants, or GIP-based hybrid peptide therapeutics.