title: Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.
abstract: Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo 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(8), Arg(34)) 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.
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Jesper
authors: J
authors: Lau
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Paw
authors: P
authors: Bloch
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Lauge
authors: L
authors: Schäffer
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Ingrid
authors: I
authors: Pettersson
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Jane
authors: J
authors: Spetzler
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Jacob
authors: J
authors: Kofoed
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Kjeld
authors: K
authors: Madsen
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Lotte Bjerre
authors: LB
authors: Knudsen
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: James
authors: J
authors: McGuire
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Dorte Bjerre
authors: DB
authors: Steensgaard
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Holger Martin
authors: HM
authors: Strauss
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Dorte X
authors: DX
authors: Gram
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Sanne Møller
authors: SM
authors: Knudsen
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Flemming Seier
authors: FS
authors: Nielsen
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Peter
authors: P
authors: Thygesen
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Steffen
authors: S
authors: Reedtz-Runge
authors: Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors: Thomas
authors: T
authors: Kruse
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D018360:Crystallography, X-Ray; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D004763:Glucagon-Like Peptides / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007279:Injections, Subcutaneous; D000069450:Liraglutide / Q000494:pharmacology; D008297:Male; D008820:Mice, Obese; D008958:Models, Molecular; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013552:Swine; D013556:Swine, Miniature; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000099194:Semaglutide
chemical_list: D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides; D000069450:Liraglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000099194:Semaglutide