TY - JOUR
T1 - Biochemical, pharmaceutical and therapeutic properties of long-acting lithocholic acid derivatized exendin-4 analogs
AU - Chae, Su Young
AU - Jin, Cheng Hao
AU - Shin, Jae Hee
AU - Son, Sohee
AU - Kim, Tae Hyung
AU - Lee, Seulki
AU - Youn, Yu Seok
AU - Byun, Youngro
AU - Lee, Myung Shik
AU - Lee, Kang Choon
N1 - Funding Information:
This work was supported by the Korean Research Foundation Grant funded by the Korean Government (MOEHRD) (# KRF-2006-353-E00022 to SYChae), and the Ministry of Education, Science and Technology in Korea ( 2009-0081871 ).
PY - 2010/3
Y1 - 2010/3
N2 - 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.
AB - 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.
KW - Bioconjugation
KW - Exendin-4
KW - GLP-1 receptor agonists
KW - Lithocholic acid
KW - Type 2 diabetic mellitus
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U2 - 10.1016/j.jconrel.2009.10.025
DO - 10.1016/j.jconrel.2009.10.025
M3 - Article
C2 - 19900495
AN - SCOPUS:76749088319
SN - 0168-3659
VL - 142
SP - 206
EP - 213
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 2
ER -