Structure-activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: importance of fatty acid length, polarity, and bulkiness.
We here report a series of derivatives describing the structure-activity relationship around liraglutide, a once-daily human glucagon-like peptide-1 fatty acid derivative, with respect to potency as well as protraction in vivo. The spacer region between the fatty acid and the peptide is mostly important for potency, whereas the fatty acid or fatty acid mimetic is important for both potency and protraction. The length of the fatty acid is the most important parameter for protraction.
Madsen
Kjeld
K
Department of Protein Engineering, Novo Nordisk, Novo Nordisk Park, Maaloev, Denmark.
Knudsen
Lotte Bjerre
LB
Agersoe
Henrik
H
Nielsen
Per Franklin
PF
Thøgersen
Henning
H
Wilken
Michael
M
Johansen
Nils Langeland
NL
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D000069450:Liraglutide; D008969:Molecular Sequence Data; D018027:Receptors, Glucagon / Q000819:agonists; D013329:Structure-Activity Relationship; D013552:Swine
D005227:Fatty Acids; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP