Design and synthesis of conformationally constrained glucagon analogues

Dev Trivedi, Ying Lin, Jung Mo Ahn, Mara Siegel, Nevena N. Mollova, Karl H. Schram, Victor J. Hruby

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Glucagon was systematically modified by forming lactam bridges within the central region of the molecule to give conformationally constrained cyclic analogues. Six cyclic glucagon analogues have been designed and synthesized. They are c[Asp9,Lys12][Lys17,18,Glu21]glucagon-NH2 (1), c[Asp9,Lys12]glucagon-NH2 (2), c[Lys12,Asp15]glucagon-NH2 (3), c[Asp15,Lys18]glucagon-NH2 (4), [Lys17-c[Lys18,Glu21]glucagon-NH2 (5), and c[Lys12,Asp21]glucagon-NH2 (6). The receptor binding potencies and receptor second messenger activities were determined by radio-receptor binding assays and adenylate cyclase assays, respectively, using rat liver plasma membranes. Most interestingly, analogues 1, 2, 3, and 4 were antagonists of glucagon stimulated adenylate cyclase activity, whereas analogues 5 and 6 were partial agonists in the functional assay. All of the cyclic analogues were found to have reduced binding potencies relative to glucagon. The structural features that might be responsible for these effects were studied using circular dichroism spectroscopy and molecular modeling. These results demonstrated the significant modulations of both receptor binding affinity and transduction (adenylate cyclase activity) that can accompany regional conformational constraints even in larger polypeptide ligands. These studies suggest that the entire molecular conformation, including the flexible middle portion, is important for molecular recognition and transduction at the hepatic glucagon receptor.

Original languageEnglish (US)
Pages (from-to)1714-1722
Number of pages9
JournalJournal of Medicinal Chemistry
Volume43
Issue number9
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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