Paper Citing NAMD - Abstract
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.
Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 103:175-184, OCT 20 2015
Type 2 diabetes mellitus (T2DM) results from compromised pancreatic beta-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 alpha-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 alpha-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 silica 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. (C) 2015 Elsevier Masson SAS. All rights reserved.
