ArticleJournal of medicinal chemistry2024
Influence of Trp-Cage on the Function and Stability of GLP-1R Agonist Exenatide Derivatives.
Article in Journal of medicinal chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Multicomponent Stapling of Glucagon-Like Peptide-1 Enables Receptor-Guided PROTAC Delivery.Angewandte Chemie (International ed. in English) · 2026Article
- Investigating transthyretin variants H88R and I107V in amyloid priming: From destabilization to complete dissociation.The FEBS journal · 2026Article
- Structural Dynamics of GLP-1 Analogues: Folding Energetics, Lipidation-Driven Assembly, and Aggregation Mechanisms.Molecules (Basel, Switzerland) · 2026Review
- Protein-Ligand Interactions in Cardiometabolic Drug Targets: Focus on Weight Loss and Cardioprotection.Molecules (Basel, Switzerland) · 2025Review
- Advances in Peptidomimetics for Next-Generation Therapeutics: Strategies, Modifications, and Applications.Chemical reviews · 2025Review
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Authors and funding
6 authors.
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Abstract
Exenatide (Ex4), a GLP-1 incretin mimetic polypeptide, is an effective therapeutic agent against diabetes and obesity. We highlight the indirect role of Ex4's structure-stabilizing Trp-cage (Tc) motif in governing GLP-1 receptor (GLP-1R) signal transduction. We use various Ex4 derivatives to explore how Tc compactness influences thermal stability, aggregation, enhancement of insulin secretion, and GLP-1R binding. We found that Ex4 variants decorated with fortified Tc motifs exhibit increased resistance to unfolding and aggregation but show an inverse relationship between the bioactivity and stability. Molecular dynamics simulations coupled with a rigid-body segmentation protocol to analyze dynamic interconnectedness revealed that the constrained Tc motifs remain intact within the receptor-ligand complexes but interfere with one of the major stabilizing contacts and recognition loci on the extracellular side of GLP-1R, dislodging the N-terminal activating region of the hormone mimetics, and restrict the free movement of TM6, the main signal transduction device of GLP-1R.
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