ABSTRACT
Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid peptide hormone that contributes to the physiological regulation of glucose homeostasis and food intake. Herein, we report the discovery of a novel class of 11 amino acid GLP-1 receptor agonists. These peptides consist of a structurally optimized 9-mer, which is closely related to the N-terminal 9 amino acids of GLP-1, linked to a substituted C-terminal biphenylalanine (BIP) dipeptide. SAR studies resulted in 11-mer GLP-1R agonists with similar in vitro potency to the native 30-mer. Peptides 21 and 22 acutely reduced plasma glucose excursions and increased plasma insulin concentrations in a mouse model of diabetes. These peptides also showed sustained exposures over several hours in mouse and dog models. The described 11-mer GLP-1 receptor agonists represent a new tool in further understanding GLP-1 receptor pharmacology that may lead to novel antidiabetic agents.
Subject(s)
Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Oligopeptides/chemistry , Oligopeptides/pharmacology , Receptors, Glucagon/agonists , Amino Acid Sequence , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Dose-Response Relationship, Drug , Glucagon-Like Peptide-1 Receptor , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Male , Mice , Models, Molecular , Molecular Sequence Data , Oligopeptides/chemical synthesis , Oligopeptides/pharmacokinetics , Protein ConformationABSTRACT
Protease activated receptor-1 (PAR-1) is a G-coupled receptor cleaved by thrombin and other proteases to expose a new N-terminus, a "tethered ligand", that activates the receptor. Independently of proteolytic cleavage, peptides similar to the new N-terminus also activate the receptor, and structure activity relationships for the activating peptides have been extensively studied. Modification of activating peptides led to rationally designed peptide antagonists. The more potent peptide antagonists were N-terminal and 3-position modifications of the agonist peptides. The resulting PAR-1 antagonists have proved useful in pharmacological studies resolving the contribution of PAR-1 signaling mechanisms relative to other PARs in platelets, vascular endothelial and other cell types. High affinity peptide agonists and antagonists have been radiolabled and proven useful in binding assays. Screening of combinatorial libraries and compound collections using the radioligands have identified non-peptide antagonists of several different chemotypes. When the "thrombin receptor" (PAR-1) was first cloned and its mechanism of activation elucidated, there was great enthusiasm for the receptor as a drug target. The use of peptide agonists and antagonists has made possible much progress in our understanding of the role of this receptor.
