1 research outputs found
Discovery of the Once-Weekly Glucagon-Like Peptide‑1 (GLP-1) Analogue Semaglutide
Liraglutide
is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds
to serum albumin <i>in vivo</i> and is approved for once-daily treatment of diabetes as well as obesity. The aim of the present
studies was to design a once weekly GLP-1 analogue by increasing albumin
affinity and secure full stability against metabolic degradation.
The fatty acid moiety and the linking chemistry to GLP-1 were the
key features to secure high albumin affinity and GLP-1 receptor (GLP-1R)
potency and in obtaining a prolonged exposure and action of the GLP-1
analogue. Semaglutide was selected as the optimal once weekly candidate.
Semaglutide has two amino acid substitutions compared to human GLP-1
(Aib<sup>8</sup>, Arg<sup>34</sup>) and is derivatized at lysine 26.
The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold
decreased compared to liraglutide, whereas the albumin affinity was
increased. The plasma half-life was 46.1 h in mini-pigs following i.v.
administration, and semaglutide has an MRT of 63.6 h after s.c. dosing
to mini-pigs. Semaglutide is currently in phase 3 clinical testing