User:Ananya Narayanan/Sandbox 1

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Background

The glucagon-like peptide-1 receptor (GLP-1R) is a Class B1 GPCR essential for maintaining glucose homeostasis, regulating appetite, and supporting metabolic health. Activation of GLP-1R by the endogenous hormone GLP-1 enhances insulin secretion, slows gastric emptying, and promotes satiety.

Current GLP-1R therapeutics are peptide-based drugs, which are effective but require injection and often cause gastrointestinal side effects that reduce long-term patient adherence. These limitations have driven major interest in developing orally available small-molecule agonists capable of reproducing the beneficial actions of GLP-1.

Recent structural and pharmacological studies show that small molecules can bind and activate GLP-1R in ways that differ from peptide ligands. Some compounds, such as PF-06882961, closely mimic GLP-1–like signaling, while others exhibit strong pathway selectivity (biased agonism). Understanding these structural differences is crucial for designing next-generation oral GLP-1R agonists with improved efficacy, safety, and tolerability.

Disease

Relevance

Structural highlights

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