Helixconstraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not beta-arrestin 2 signaling

Plisson, Fabien, Hill, Timothy A., Mitchell, Justin M., Hoang, Huy N., de Araujo, Aline D., Xu, Weijun, Cotterell, Adam, Edmonds, David J., Stanton, Robert V., Derksen, David R., Loria, Paula M., Griffith, David A., Price, David A., Liras, Spiros and Fairlie, David P. (2017) Helixconstraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not beta-arrestin 2 signaling. European Journal of Medicinal Chemistry, 127 703-714. doi:10.1016/j.ejmech.2016.10.044

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads

Author Plisson, Fabien
Hill, Timothy A.
Mitchell, Justin M.
Hoang, Huy N.
de Araujo, Aline D.
Xu, Weijun
Cotterell, Adam
Edmonds, David J.
Stanton, Robert V.
Derksen, David R.
Loria, Paula M.
Griffith, David A.
Price, David A.
Liras, Spiros
Fairlie, David P.
Title Helixconstraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not beta-arrestin 2 signaling
Journal name European Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0223-5234
1768-3254
Publication date 2017-02-01
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.ejmech.2016.10.044
Open Access Status Not yet assessed
Volume 127
Start page 703
End page 714
Total pages 12
Place of publication Issy les Moulineaux, Cedex, France
Publisher Elsevier Masson
Language eng
Formatted 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.
Keyword GLP-1
Beta arrestin-2
Insulin-release
Diabetes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 0 times in Thomson Reuters Web of Science Article
Scopus Citation Count Cited 0 times in Scopus Article
Google Scholar Search Google Scholar
Created: Mon, 05 Dec 2016, 23:33:16 EST by Susan Allen on behalf of Institute for Molecular Bioscience