posted on 2021-03-06, 16:29authored byIan 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
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.