Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability

Biochem Pharmacol. 2007 Jan 1;73(1):84-93. doi: 10.1016/j.bcp.2006.09.013. Epub 2006 Sep 17.

Abstract

PEGylation has been considered to be a good biotechnique for improving the therapeutic value of glucagon-like peptide-1 (GLP-1) analogs for the treatment of type 2 diabetes. Despite the attractive anti-diabetic potentials, GLP-1 does not exert its full biological action because of its extremely short life-time in vivo due to rapid proteolytic degradation. Here, the enzyme-resistant mono-PEGylated GLP-1 isomers substituted at Lys(26)- or Lys(34)-amine were prepared through a newly devised site-specific PEGylation process using a maleic anhydride-protection/deprotection method. The therapeutic potentials of these site-specific PEGylated GLP-1 isomers (Lys(26)- or Lys(34)-PEG-GLP-1) along with His(7)-(N-terminus) PEG-GLP-1 were evaluated by examining their insulinotropic activity, glucose-stabilizing capability, and proteolytic stability. Lys(34)-PEG-GLP-1 was found to have the well-preserved insulinotropic activity (93% efficacy versus GLP-1) in isolated rat pancreatic islets. Furthermore, Lys(34)-PEG-GLP-1 showed the most prominent glucose-stabilizing capability, evaluated via an oral glucose tolerance test in db/db mice by considering the following three crucial factors: (i) maximum blood glucose level (BGL), (ii) required time to lower the BGL below 100mg/dl, and (iii) total hypoglycemic degree. Additionally, Lys(34)-PEG-GLP-1 had longer half-lives than the other PEGylated GLP-1s in the dipeptidyl peptidase IV (DPP IV) inhibitor-treated liver or kidney homogenate, and its stability against DPP IV was also comparable to that of Lys(26)-PEG-GLP-1. Taken together, Lys(34)-PEG-GLP-1 displayed the promising characteristics in all evaluations versus His(7)- or Lys(26)-PEG-GLP-1. This site-specific PEGylated GLP-1 analog would have therapeutic usefulness for treating type 2 diabetes on account of the well-preserved insulinotropic activity, the increased proteolytic stability, and thereby the improved glucose-stabilizing capability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Drug Evaluation, Preclinical
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide 1 / therapeutic use
  • Hydrolysis
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Polyethylene Glycols / chemistry*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • Polyethylene Glycols
  • Glucagon-Like Peptide 1