title: A glucagon analog chemically stabilized for immediate treatment of life-threatening hypoglycemia.
abstract: For more than half a century glucagon has been used as a critical care medicine in the treatment of life-threatening hypoglycemia. It is commercially supplied as a lyophilized powder intended to be solubilized in dilute aqueous hydrochloric acid immediately prior to administration. We have envisioned a "ready-to-use" glucagon as a drug of more immediate and likely use. Through a series of iterative changes in the native sequence we have identified glucagon analogs of appreciably enhanced aqueous solubility at physiological pH, and of chemical stability suitable for routine medicinal use. The superior biophysical properties were achieved in part through adjustment of the isoelectric point by use of a C-terminal Asp-Glu dipeptide. The native glutamines at positions 3, 20 and 24 as well as the methionine at 27 were substituted with amino acids of enhanced chemical stability, as directed by a full alanine scan of the native hormone. Of utmost additional importance was the dramatically enhanced stability of the peptide when Ser16 was substituted with alpha,aminoisobutyric acid (Aib), a substitution that stabilizes peptide secondary structure. The collective set of changes yield glucagon analogs of comparable in vitro and in vivo biological character to native hormone but with biophysical properties much more suitable for clinical use.
authors.affiliation: Indiana University, Department of Chemistry, Bloomington, IN 47405, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Chabenne
authors.affiliation: Indiana University, Department of Chemistry, Bloomington, IN 47405, USA.
authors.forename: Maria Dimarchi
authors.initials: MD
authors.lastname: Chabenne
authors.affiliation: Indiana University, Department of Chemistry, Bloomington, IN 47405, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Indiana University, Department of Chemistry, Bloomington, IN 47405, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Levy
authors.affiliation: Indiana University, Department of Chemistry, Bloomington, IN 47405, USA.
authors.forename: David
authors.initials: D
authors.lastname: Smiley
authors.affiliation: Indiana University, Department of Chemistry, Bloomington, IN 47405, USA.
authors.forename: Vasily
authors.initials: V
authors.lastname: Gelfanov
authors.affiliation: Indiana University, Department of Chemistry, Bloomington, IN 47405, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Dimarchi
keywords: Glucagon; Hypoglycemia; Insulin-dependent diabetes; Peptide synthesis
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