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 journalArticlepeer-review


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
Issue number2
StatePublished - Mar 2010
Externally publishedYes


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

ASJC Scopus subject areas

  • Pharmaceutical Science


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