Abstract
The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein–coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain–binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.
Highlights
Glucagon-like peptide (GLP)-1 is a gastrointestinal peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, a cells in the pancreas, and the central nervous system, which has multiple therapeutic effects useful in the management of type 2 diabetes mellitus (T2DM)
The first glucagon receptor (GCGR) 7TMD structure (PDB: 4L6R) was solved with an N-terminal fusion partner fused at residue 123 (Siu et al, 2013), and it is this structure that is of particular interest to understand glucagon-like peptide (GLP)-1R because both the receptors and native ligands are closely related
As the duration of GLP-1 receptor (GLP-1R) agonist action is extended with peptides like albiglutide, dulaglutide, long-acting release exenatide, or liraglutide, the impact on blood glucose levels is enhanced as insulinotropic action and activity to reduce glucagon become more prominent than the effect on gastric emptying
Summary
Glucagon-like peptide (GLP)-1 is a gastrointestinal peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, a cells in the pancreas, and the central nervous system, which has multiple therapeutic effects useful in the management of type 2 diabetes mellitus (T2DM) These include most prominently a glucose-dependent insulinotropic function and other actions on glucose homeostasis, as well as benefits to gastric emptying and appetite regulation valuable in reducing food intake and body weight. We discuss the peptide analogs and nonpeptidic ligands that have been developed to target GLP1R, the molecular basis of their action, and the implications for ligand-biased activity and allosteric regulation of this hormone-receptor system Some of these GLP-1R agonists are already in clinical use, with many more currently being developed, and likely to provide enhancements in their ease of administration, tolerability, and effectiveness
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