Fig. 7.

Nonpeptidic GLP-1R modulators and peptide mimetics. Liraglutide (Novo Nordisk) was the first approved human GLP-1 analog to teat diabetes (European Union, 2009; United States, 2010) and obesity (United States, 2014; European Union, 2015). Liraglutide has 97% sequence homology to human GLP-1 and was designed to reversibly bind to albumin by attachment of palmatic acid via a L-γ-glutamic linker to lys²⁶ in Arg³⁴ GLP-1_7–37. The modification of Lys³⁴ to Arg³⁴ made it possible to produce Arg³⁴ GLP-1_7–37 in yeast, followed by acylation of Lys²⁶. The native GLP-1 peptide has a half-life of approximately 2 minutes due to rapid cleavage of GLP-1_7–37 to GLP-1_9–37 by DPP-4 (Deacon et al., 1995a,b; Vilsboll et al., 2003). Liraglutide comprises the natural GLP-1 N terminus, but has a half-life of about 11 hours after s.c. dosing to humans combined with a delayed absorption from sub cutis that gives a pharmacokinetic profile applicable for once-daily administration. The reason for extended circulation is due to reversible albumin binding that protects from DPP-4 degradation and glomerular filtration, whereas the delayed absorption is explained by the ability of liraglutide to form heptamers by self-assemble controlled by the fatty acid side-chain at position 26. Liraglutide is well tolerated and capable of substantially improving glycemic control with low risk of hypoglycemia and weight loss benefit (Knudsen et al., 2000; Knudsen, 2004; Madsen et al., 2007; Steensgaard et al., 2008; Dharmalingam et al., 2011; Wang et al., 2015).