Title
Helixconstraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not beta-arrestin 2 signaling
Author
Fabien Plissona, 1, Timothy A. Hilla, , 1, , Justin M. Mitchella, Huy N. Hoanga, Aline D. de Araujoa, Weijun Xua, Adam Cotterella, David J. Edmondsb, Robert V. Stantonb, David R. Derksen, Paula M. Loria, David A. Griffith, David A. Price, Spiros Liras, David P. Fairlie
Year
2017
Journal
European Journal of Medicinal Chemistry
Abstract
Glucagon-like peptide (GLP-1) is an endogenous hormone that induces insulin secretion from pancreatic islets and modified forms are used to treat diabetes mellitus type 2. Understanding how GLP-1 interacts with its receptor (GLP-1R) can potentially lead to more effective drugs. Modeling and NMR studies of the N-terminus of GLP-1 suggest a β-turn between residues Glu9-Phe12 and a kinked alpha helix between Val16-Gly37. N-terminal turn constraints attenuated binding affinity and activity (compounds 1–8). Lys-Asp (i, i+4) crosslinks in the middle and at the C-terminus increased alpha helicity and cAMP stimulation without much effect on binding affinity or beta-arrestin 2 recruitment (compounds 9–18). Strategic positioning of helix-inducing constraints and amino acid substitutions (Tyr16, Ala22) increased peptide helicity and produced ten-fold higher cAMP potency (compounds 19–28) over GLP-1(7–37)-NH2. The most potent cAMP activator (compound 23) was also the most potent inducer of insulin secretion.
Instrument
J-710
Keywords
Circular dichroism, Secondary structure, Biochemistry