Biochemical, pharmaceutical and therapeutic properties of long-acting lithocholic acid derivatized exendin-4 analogs

Title
Biochemical, pharmaceutical and therapeutic properties of long-acting lithocholic acid derivatized exendin-4 analogs
Authors
채수영진정호신재희손소희김태형이슬기윤유석변영로이명식이강춘
Keywords
GLP-1 receptor agonists; Exendin-4; Lithocholic acid; Bioconjugation; Type 2 diabetic mellitus
Issue Date
2010-03
Publisher
Journal of controlled release
Citation
VOL 142, 206-213
Abstract
Alterations in the physicochemical characteristics of peptide drugs can transform their biological and pharmaceutical features. In the present study, we explored the potentials of lithocholic acid (LCA)-modified exendin-4 derivatives as novel long-acting GLP-1 receptor agonists. Exendin-4 was modified with lithocholic acid at two lysine residues to produce three derivatives that were obtained by reverse-phase HPLC separation, namely, Lys12-LCA-exendin-4 (LCA-M2), Lys27-LCA-exendin-4 (LCA-M1), and Lys12,27-LCAexendin- 4 (LCA-Di)). The biological, pharmacological, and physicochemical characteristics of these three exendin-4 analogues were then investigated. Although slight reductions in the GLP-1 receptor binding capacity and insulinotropic activity of exendin-4 were observed after derivatization, the mono-LCA substitutions, especially LCA-M1, well-preserved antidiabetic activity in type 2 diabetic mice when administered subcutaneously or intraperitoneally. Furthermore, the pharmacokinetic characteristics were dramatically enhanced, that is, absorption was delayed and elimination half-life was increased (1.6±0.4 and 9.7±1.4 h by exendin-4 and LCA-M1, respectively). The enhanced long-acting characteristics of the derivative was found to be due to albumin binding and nanoparticle formation, and these were verified by the restoration of normoglycemia in type 2 diabetic mice after single injection (N24 h, N10 nmol/kg, s.c.) and daily injections (15 nmol/kg/day) maintained normoglycemia for the 4-week administration period. Furthermore, antidiabetic potentials, such as, glucose clearance kinetics and percentage areas occupied by pancreatic β-cells were also enhanced by long-term LCA-M1 administration. The present study demonstrates that the derivatization of exendin-4 with LCA offers a possible means of producing a long-acting GLP-1 receptor agonist.
URI
https://pubs.kist.re.kr/handle/201004/38246
ISSN
0168-3659
Appears in Collections:
KIST Publication > Article
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE