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

• Published in: European journal of medicinal chemistry 2015-10, Vol.103, p.175-184
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Animals; CHO Cells; Conotoxins; Conotoxins - chemistry; Conotoxins - pharmacology; Cricetulus; Dose-Response Relationship, Drug; Exendin-4; Glucagon-like peptide-1; Glucagon-like peptide-1 receptor; Glucagon-Like Peptide-1 Receptor - agonists; Humans; Models, Molecular; Molecular Structure; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Structure-Activity Relationship; Type-2 diabetes mellitus
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.08.046

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. [Display omitted] •Chimeras combining 11 residue peptidomimetics and α-conotoxins are potent GLP-1R agonists.•Several chimeras had improved biophysical properties compared to the parent compounds.•These bicyclic peptidomimetics provide a new avenue in the development of GLP-1R agonists.