Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists

Swedberg, Joakim E., Schroeder, Christina I., Mitchell, Justin M., Durek, Thomas, Fairlie, David P., Edmonds, David J., Griffith, David A., Ruggeri, Roger B., Derksen, David R., Loria, Paula M., Liras, Spiros, Price, David A. and Craik, David J. (2015) Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists. European Journal of Medicinal Chemistry, 103 175-184. doi:10.1016/j.ejmech.2015.08.046

Author Swedberg, Joakim E.
Schroeder, Christina I.
Mitchell, Justin M.
Durek, Thomas
Fairlie, David P.
Edmonds, David J.
Griffith, David A.
Ruggeri, Roger B.
Derksen, David R.
Loria, Paula M.
Liras, Spiros
Price, David A.
Craik, David J.
Title Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists
Journal name European Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0223-5234
Publication date 2015-10-20
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.ejmech.2015.08.046
Volume 103
Start page 175
End page 184
Total pages 10
Place of publication Moulineaux, Cedex, France
Publisher Elsevier Masson SAS
Collection year 2016
Language eng
Formatted abstract
Type 2 diabetes mellitus (T2DM) results from compromised pancreatic β-cell function, reduced insulin production, and lowered insulin sensitivity in target organs resulting in hyperglycemia. The GLP-1 hormone has two biologically active forms, GLP-1-(7–37) and GLP-1-(7–36)amide, which are equipotent at the glucagon-like peptide-1 receptor (GLP-1R). These peptides are central both to normal glucose metabolism and dysregulation in T2DM. Several structurally modified GLP-1 analogues are now approved drugs, and a number of other analogues are in clinical trials. None of these compounds is orally bioavailable and all require parenteral delivery. Recently, a number of smaller peptidomimetics containing 11–12 natural and unnatural amino acids have been identified that have similar insulin regulating profiles as GLP-1. The α-conotoxins are a class of disulfide rich peptide venoms isolated from cone snails, and are known for their highly constrained structures and resistance to enzymatic degradation. In this study, we examined whether 11-residue peptidomimetics incorporated into α-conotoxin scaffolds, forming monocyclic or bicyclic compounds constrained by disulfide bonds and/or backbone cyclization, could activate the GLP-1 receptor (GLP-1R). Several compounds showed potent (nanomolar) agonist activity at GLP-1R, as evaluated via cAMP signaling. In addition, HPLC retention times and in silico calculations suggested that mono- and bicyclic compounds had more favorable n-octanol/water partition coefficients according to the virtual partition coefficient model (vLogP), while maintaining a smaller radius of gyration compared to corresponding uncyclized peptidomimetics. Our findings suggest that cyclic peptidomimetics provide a potential avenue for future design of potent, compact ligands targeting GLP-1R and possessing improved physicochemical properties.
Keyword Conotoxins
Exendin 4
Glucagon like peptide 1
Glucagon like peptide-1 receptor
Type 2 Diabetes Mellitus
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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 1 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 18 Sep 2015, 12:41:41 EST by Susan Allen on behalf of Institute for Molecular Bioscience