Open AccessSynthesis, Optimization, and Biological Evaluation of Corrinated Conjugates of the GLP-1R Agonist Exendin-4
Author(s) -
Ian C. Tinsley,
Tito Borner,
MacKenzie L. Swanson,
Oleg G. Chepurny,
Sarah Doebley,
Varun Kamat,
Ian R. Sweet,
George G. Holz,
Matthew R. Hayes,
Bart C. De Jonghe,
Robert P. Doyle
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00185
Subject(s) - chemistry , conjugate , agonist , in vivo , stereochemistry , partial agonist , pharmacology , corrin , receptor , biochemistry , vitamin b12 , medicine , mathematical analysis , mathematics , microbiology and biotechnology , biology
Corrination is the conjugation of a corrin ring containing molecule, such as vitamin B 12 (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.