【文章名】Design and Synthesis of Conformationally Constrained Glucagon-Like Peptide-1 Derivatives with Increased Plasma Stability and Prolonged in Vivo Activity.
Design and Synthesis of Conformationally Constrained Glucagon-Like Peptide-1 Derivatives with Increased Plasma Stability and Prolonged in Vivo Activity.
作者
Miranda, Les P.;Winters, Katherine A.;Gegg, Colin V.;Patel, Ankita;Aral, Jennifer;Long, Jason;Zhang, Jingwen;Diamond, Stephanie;Guido, Mark;Stanislaus, Shanaka;Ma, Mark;Li, Hongyan;Rose, Mark J.;Poppe, Leszek;Veniant, Murielle M.;
[摘要]：A series of conformationally constrained derivs. 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 derivs. 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 prepd. The effect of a helix-promoting a-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 binding properties. Importantly, PEGylated GLP-1 peptide 23 exhibited sustained in vivo efficacy with respect to blood glucose redn. and decreased body wt. for several days in nonhuman primates.
