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PDBsum entry 4zgm
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Signaling protein
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PDB id
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4zgm
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References listed in PDB file
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Key reference
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Title
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Discovery of the once-Weekly glucagon-Like peptide-1 (glp-1) analogue semaglutide.
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Authors
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J.Lau,
P.Bloch,
L.Schäffer,
I.Pettersson,
J.Spetzler,
J.Kofoed,
K.Madsen,
L.B.Knudsen,
J.Mcguire,
D.B.Steensgaard,
H.M.Strauss,
D.X.Gram,
S.M.Knudsen,
F.S.Nielsen,
P.Thygesen,
S.Reedtz-Runge,
T.Kruse.
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Ref.
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J Med Chem, 2015,
58,
7370-7380.
[DOI no: ]
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PubMed id
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Abstract
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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.
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