title: 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.
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.
authors.affiliation: Drug Targeting Laboratory, College of Pharmacy, SungKyunKwan University, 300 Chonchon-dong, Jangan-ku, Suwon City 440-746, Republic of Korea.
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
authors.forename: Su Young
authors.initials: SY
authors.lastname: Chae
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.forename: Jae Eun
authors.initials: JE
authors.lastname: Jeon
authors.forename: Hyong Goo
authors.initials: HG
authors.lastname: Shin
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006868:Hydrolysis; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011092:Polyethylene Glycols; D052216:Glucagon-Like Peptide 1