Glucagon-like peptide-1（GLP-1） is an endogenous insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV（DPP-IV）. To...Glucagon-like peptide-1（GLP-1） is an endogenous insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV（DPP-IV）. To overcome this problem, various N-terminal modifications of GLP-1 have been performed to prolong the in vivo biological activity, by improving the DPP-IV resistance while retaining receptor affinity and receptor activation. These studies have included modifications of His7, Ala8 or Glu9 at the N-terminus of GLP-1 and some other modifications. Among them, Ala8 substitutions with glycine（Gly8） and α-aminoisobutyric acid（Aib8） have been clinically applied in the development of diabetic therapy, such as Exenatide, Semaglutide, Albiglutide and Taspoglutide. In this review, we introduce N-terminal modifications of GLP-1 that have been reported, and discuss their potential and challenges for the treatment of type 2 diabetes.展开更多
As a glucagon(GCG) receptor(GCGR) and glucagon-like peptide 1(GLP-1) receptor(GLP-1R) dual agonist, oxyntomodulin(OXM) has been attracting scientific attentions due to its efficacies of suppressing appetite, increasin...As a glucagon(GCG) receptor(GCGR) and glucagon-like peptide 1(GLP-1) receptor(GLP-1R) dual agonist, oxyntomodulin(OXM) has been attracting scientific attentions due to its efficacies of suppressing appetite, increasing energy expenditure, and inducing body weight loss in obese humans. Based on the scaffold of native OXM, specific helix-favoring amino acids substitutions and the consequent salt bridge formations were believed to offer enhanced and balanced GCGR/GLP-1R activations through increasing α-helical conformation. Novel OXM analogues are obtained by intramolecular lactam stapling of positions[Glu16 & Lys20] or [Lys17 & Glu21] to further strengthen conformationally constrained stabilization. Even though the lactam staple does not provide additional dual GCGR/GLP-1R activations in vitro, the stapled OXM analogues are firstly reported to have higher or lower anti-PANC-1 cell proliferation activity, meanwhile which has no obvious inhibitory effect on the proliferation of He La cells. Therefore, it is speculated that the stapled analogues may have the potential to inhibit the proliferation of specific cancer cell types.Among the stapled peptides as well as their precursors, analogue 6 has the most prominent anti-PANC-1 proliferation activity with the IC50value of 115.1 μmol/L. Its mechanism of actions including effective signal pathways should be worth further investigations in future.展开更多
文摘Glucagon-like peptide-1（GLP-1） is an endogenous insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV（DPP-IV）. To overcome this problem, various N-terminal modifications of GLP-1 have been performed to prolong the in vivo biological activity, by improving the DPP-IV resistance while retaining receptor affinity and receptor activation. These studies have included modifications of His7, Ala8 or Glu9 at the N-terminus of GLP-1 and some other modifications. Among them, Ala8 substitutions with glycine（Gly8） and α-aminoisobutyric acid（Aib8） have been clinically applied in the development of diabetic therapy, such as Exenatide, Semaglutide, Albiglutide and Taspoglutide. In this review, we introduce N-terminal modifications of GLP-1 that have been reported, and discuss their potential and challenges for the treatment of type 2 diabetes.
文摘As a glucagon(GCG) receptor(GCGR) and glucagon-like peptide 1(GLP-1) receptor(GLP-1R) dual agonist, oxyntomodulin(OXM) has been attracting scientific attentions due to its efficacies of suppressing appetite, increasing energy expenditure, and inducing body weight loss in obese humans. Based on the scaffold of native OXM, specific helix-favoring amino acids substitutions and the consequent salt bridge formations were believed to offer enhanced and balanced GCGR/GLP-1R activations through increasing α-helical conformation. Novel OXM analogues are obtained by intramolecular lactam stapling of positions[Glu16 & Lys20] or [Lys17 & Glu21] to further strengthen conformationally constrained stabilization. Even though the lactam staple does not provide additional dual GCGR/GLP-1R activations in vitro, the stapled OXM analogues are firstly reported to have higher or lower anti-PANC-1 cell proliferation activity, meanwhile which has no obvious inhibitory effect on the proliferation of He La cells. Therefore, it is speculated that the stapled analogues may have the potential to inhibit the proliferation of specific cancer cell types.Among the stapled peptides as well as their precursors, analogue 6 has the most prominent anti-PANC-1 proliferation activity with the IC50value of 115.1 μmol/L. Its mechanism of actions including effective signal pathways should be worth further investigations in future.
