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

Su Young Chae, Cheng Hao Jin, Jae Hee Shin, Sohee Son, Tae Hyung Kim, Seulki Lee, Yu Seok Youn, Youngro Byun, Myung Shik Lee, Kang Choon Lee

Research output: Contribution to journalArticle

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-LCA-exendin-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±1.4h 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 (>24h, >10nmol/kg, s.c.) and daily injections (15nmol/kg/day) maintained normoglycemia for the 4-week administration period. Furthermore, antidiabetic potentials, such as, glucose clearance kinetics and percentage areas 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.

Original languageEnglish (US)
Pages (from-to)206-213
Number of pages8
JournalJournal of Controlled Release
Volume142
Issue number2
DOIs
Publication statusPublished - Mar 2010
Externally publishedYes

    Fingerprint

Keywords

  • Bioconjugation
  • Exendin-4
  • GLP-1 receptor agonists
  • Lithocholic acid
  • Type 2 diabetic mellitus

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this