Synthesis, Optimization, and Biological Evaluation of Corrinated Conjugates of the GLP-1R Agonist Exendin-4

Ian C. Tinsley, Tito Borner, MacKenzie L. Swanson, Oleg G. Chepurny, Sarah A. Doebley, Varun Kamat, Ian R. Sweet, George G. Holz, Matthew R. Hayes, Bart C. De Jonghe, Robert P. Doyle

Research output: Contribution to journalArticlepeer-review

Abstract

Corrination is the conjugation of a corrin ring containing molecule, such as vitamin B12 (B12) or B12 biosynthetic precursor dicyanocobinamide (Cbi), to small molecules, peptides, or proteins with the goal of modifying pharmacology. Recently, a corrinated GLP-1R agonist (GLP-1RA) exendin-4 (Ex4) has been shown in vivo to have reduced penetration into the central nervous system relative to Ex4 alone, producing a glucoregulatory GLP-1RA devoid of anorexia and emesis. The study herein was designed to optimize the lead conjugate for GLP-1R agonism and binding. Two specific conjugation sites were introduced in Ex4, while also utilizing various linkers, so that it was possible to identify Cbi conjugates of Ex4 that exhibit improved binding and agonist activity at the GLP-1R. An optimized conjugate (22), comparable with Ex4, was successfully screened and subsequently assayed for insulin secretion in rat islets and in vivo in shrews for glucoregulatory and emetic behavior, relative to Ex4.

Original languageEnglish (US)
Pages (from-to)3479-3492
Number of pages14
JournalJournal of Medicinal Chemistry
Volume64
Issue number6
DOIs
StatePublished - Mar 25 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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