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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cholic Acids / chemical synthesis*
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Cholic Acids / pharmacokinetics
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Cholic Acids / pharmacology
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Deoxycholic Acid / analogs & derivatives
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Deoxycholic Acid / chemical synthesis
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Deoxycholic Acid / pharmacokinetics
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Deoxycholic Acid / pharmacology
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Diabetes Mellitus, Type 2 / drug therapy
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Exenatide
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Glucagon-Like Peptide-1 Receptor
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Glucose Tolerance Test
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Hydrophobic and Hydrophilic Interactions
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology
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In Vitro Techniques
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Islets of Langerhans / drug effects
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Islets of Langerhans / metabolism
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Lithocholic Acid / analogs & derivatives
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Lithocholic Acid / chemical synthesis
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Lithocholic Acid / pharmacokinetics
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Lithocholic Acid / pharmacology
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Male
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Mice
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Peptides / chemical synthesis*
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Peptides / pharmacokinetics
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Peptides / pharmacology
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Protein Binding
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, Glucagon / agonists*
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Serum Albumin / metabolism
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Structure-Activity Relationship
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Venoms / chemical synthesis*
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Venoms / pharmacokinetics
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Venoms / pharmacology
Substances
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Cholic Acids
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Glp1r protein, mouse
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Glp1r protein, rat
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Glucagon-Like Peptide-1 Receptor
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Hypoglycemic Agents
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Peptides
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Receptors, Glucagon
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Serum Albumin
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Venoms
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Deoxycholic Acid
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Lithocholic Acid
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Exenatide