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

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• 作者：Les P. Miranda ; Katherine A. Winters ; Colin V. Gegg ; Ankita Patel ; Jennifer Aral ; Jason Long ; Jingwen Zhang ; Stephanie Diamond ; Mark Guido ; Shanaka Stanislaus ; Mark Ma ; Hongyan Li ; Mark J. Rose ; Lesze
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：May 8, 2008
• 年：2008
• 卷：51
• 期：9
• 页码：2758 - 2765
• 全文大小：362K
• 年卷期：v.51,no.9(May 8, 2008)
• ISSN：1520-4804

文摘

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 binding properties. Importantly, PEGylated GLP-1 peptide 23 exhibited sustained in vivo efficacy with respect to blood glucose reduction and decreased body weight for several days in nonhuman primates.