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Optimization of the native glucagon sequence for medicinal purposes
Joseph R Chabenne1, Maria A DiMarchi, Vasily M Gelfanov
1Department of Chemistry, Indiana University, Bloomington, IN 47405-7102, USA.
Journal of Diabetes Science and Technology
|December 7, 2010
Summary
New glucagon analogs, D28 and Cex, show improved solubility and stability at physiological pH. These findings support their potential development as ready-to-use medications for hypoglycemia treatment.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Endocrinology
Background:
- Glucagon is essential for treating hypoglycemia but has poor solubility and stability at physiological pH.
- Current glucagon formulations are lyophilized solids requiring reconstitution, with limited stability after preparation.
- Chemical degradation occurs at extreme pH values and elevated temperatures, limiting shelf-life and usability.
Purpose of the Study:
- To identify glucagon analogs with enhanced aqueous solubility and chemical stability at physiological pH.
- To explore modifications that improve the developability of glucagon as a ready-to-use therapeutic.
- To assess the biological activity and receptor selectivity of modified glucagon analogs.
Main Methods:
- Solid-phase peptide synthesis was used to create a series of glucagon analogs.
- Physical properties (solubility, stability) were assessed using solubility assays, HPLC, and mass spectrometry.
- Biochemical properties were evaluated in HEK293 cells expressing glucagon or GLP-1 receptors.
Main Results:
- Substitution of asparagine-28 with aspartic acid (D28) significantly increased solubility at physiological pH.
- C-terminal extension (Cex) with an exendin-based sequence also dramatically enhanced solubility.
- Both D28 and Cex analogs retained high potency and selectivity for the glucagon receptor.
Conclusions:
- Developing glucagon analogs with high biological activity, selectivity, and stability presents significant challenges.
- The D28 and Cex analogs exhibit promising chemical, physical, and biochemical properties.
- These analogs warrant further investigation as potential clinical candidates for hypoglycemia treatment.
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