Design and Synthesis of Conformationally Constrained Glucagon-Like Peptide-1 Derivatives with Increased Plasma Stability and Prolonged in Vivo Activity

A series of conformationally constrained derivatives of glucagon-like peptide-1 (GLP-1) were designed and evaluated. By use of [Gly8]GLP-1(7–37)-NH2 (2) peptide as a starting point, 17 cyclic derivatives possessing i to i + 4, i to i + 5, or i to i + 7 side chain to side chain lactam bridges from positions 18 to 30 were prepared. The effect of a helix-promoting α-amino-isobutyric acid (Aib) substitution at position 22 was also evaluated. The introduction of i to i + 4 glutamic acid−lysine lactam constraints in c[Glu18-Lys22][Gly8]GLP-1(7–37)-NH2 (6), c[Glu22-Lys26][Gly8]GLP-1(7–37)-NH2 (10), and c[Glu23-Lys27][Gly8]GLP-1(7–37)-NH2 (11) resulted in potent functional activity and receptor affinities comparable to native GLP-1. Selected GLP-1 peptides were chemoselectively PEGylated in order to prolong their in vivo activity. PEGylated peptides [Gly8,Aib22]GLP-1(7–37)-Cys(PEG)-Ala-NH2 (23) and c[Glu22-Lys26][Gly8]GLP-1(7–37)-Cys(PEG)-Ser-Gly-NH2 (24) retained picomolar functional potency and avid receptor bi...