title: Preparation and structural, biochemical, and pharmaceutical characterizations of bile acid-modified long-acting exendin-4 derivatives.
abstract: To develop an effective long-acting antidiabetic, the GLP-1 analogue of exendin-4 was modified with three different bile acids (BAs; cholic, deoxycholic, or lithocholic acid), at its two lysine residues. The biological, pharmaceutical, and physicochemical characteristics of these exendin-4 analogues were carefully investigated. Biological activity tests demonstrated that the monobile acid substitutions of exendin-4 showed well preserved receptor binding efficacy without noticeable insulinotropic or antidiabetic activity loss. However, physicochemical and pharmacokinetic studies revealed that the albumin-binding properties and in vivo elimination half-lives of BAM1-Ex4s (Lys(27)-BA-Ex4s) were significantly enhanced by increasing the hydrophobicities of the conjugated BAs. Furthermore, the protracted antidiabetic effects of the BAM1-Ex4s were also verified by the prolonged restoration of normoglycemia in type 2 diabetic mice. Accordingly, the present study suggests that the derivatization of exendin-4 with BAs offers a means of producing long-acting GLP-1 receptor agonists for type 2 diabetic therapy.
authors.affiliation: College of Pharmacy, SungKyunKwan University, 300 Chonchon-dong, Jangan-gu, Suwon 440-746, Korea.
authors.forename: Sohee
authors.initials: S
authors.lastname: Son
authors.forename: Su Young
authors.initials: SY
authors.lastname: Chae
authors.forename: Chang Wan
authors.initials: CW
authors.lastname: Kim
authors.forename: Yang Gyu
authors.initials: YG
authors.lastname: Choi
authors.forename: Sung Youb
authors.initials: SY
authors.lastname: Jung
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002793:Cholic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D003840:Deoxycholic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008095:Lithocholic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D010455:Peptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists*; D012709:Serum Albumin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014688:Venoms / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D002793:Cholic Acids; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D012709:Serum Albumin; D014688:Venoms; D003840:Deoxycholic Acid; D008095:Lithocholic Acid; D000077270:Exenatide