Cyclic alpha-conotoxin peptidomimetic chimeras as potent GLP-1R agonists.
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.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Joakim E
JE
Swedberg
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Christina I
CI
Schroeder
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Justin M
JM
Mitchell
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Thomas
T
Durek
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
David P
DP
Fairlie
Worldwide Medicinal Chemistry, CVMED, Pfizer Inc., Cambridge, MA, USA.
David J
DJ
Edmonds
Worldwide Medicinal Chemistry, CVMED, Pfizer Inc., Cambridge, MA, USA.
David A
DA
Griffith
Worldwide Medicinal Chemistry, CVMED, Pfizer Inc., Cambridge, MA, USA.
Roger B
RB
Ruggeri
Pharmacokinetics, Dynamics and Metabolism, Worldwide Research & Development, Pfizer Inc., Groton, CT, USA.
David R
DR
Derksen
Pharmacokinetics, Dynamics and Metabolism, Worldwide Research & Development, Pfizer Inc., Groton, CT, USA.
Paula M
PM
Loria
Worldwide Medicinal Chemistry, CVMED, Pfizer Inc., Cambridge, MA, USA.
Spiros
S
Liras
Worldwide Medicinal Chemistry, CVMED, Pfizer Inc., Cambridge, MA, USA.
David A
DA
Price
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia. Electronic address: d.craik@imb.uq.edu.au.
David J
DJ
Craik
D000818:Animals; D016466:CHO Cells; D020916:Conotoxins / Q000737:chemistry* / Q000494:pharmacology*; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067757:Glucagon-Like Peptide-1 Receptor
D020916:Conotoxins; D057786:Peptidomimetics; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor
Conotoxins; Exendin-4; Glucagon-like peptide-1; Glucagon-like peptide-1 receptor; Type-2 diabetes mellitus