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Related Concept Videos

Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

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Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
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Insulin secretory vesicles release insulin to stimulate blood glucose uptake and regulate carbohydrate metabolism. When the blood glucose levels increase, glucose enters the pancreatic β-islet cells through glucose transporters. Once inside, glucose is metabolized through glycolysis, the citric acid cycle, and the electron transport chain, producing ATP. This increase in ATP concentration closes ATP-sensitive potassium channels, leading to depolarization of the membrane and the opening of...
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Receptor-mediated Endocytosis01:39

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Real-time Analysis of Gut-brain Neural Communication: Cortex wide Calcium Dynamics in Response to Intestinal Glucose Stimulation
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Prolonged Activation of the GLP-1 Receptor via Covalent Capture.

Özge Ünsal1, Z Selin Bacaksiz1, Vladislav Khamraev1

  • 1Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States.

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Researchers designed a novel glucagon-like peptide-1 (GLP-1) analogue that covalently binds to the GLP-1 receptor (GLP-1R). This modification significantly prolongs receptor activation, offering a promising strategy for developing more effective metabolic disease treatments.

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Area of Science:

  • Endocrinology and Metabolism
  • Medicinal Chemistry
  • Molecular Pharmacology

Background:

  • Glucagon-like peptide-1 (GLP-1) is a crucial gut hormone regulating glucose homeostasis and promoting weight loss.
  • Native GLP-1 has a short in vivo half-life, limiting its therapeutic potential.
  • GLP-1 receptor (GLP-1R) agonism underlies the beneficial metabolic effects of GLP-1 and its derivatives.

Purpose of the Study:

  • To design and develop long-lived GLP-1 receptor agonists.
  • To investigate the potential of covalent cross-linking for prolonged GLP-1R activation.

Main Methods:

  • Structure-guided design of peptide analogues incorporating an electrophilic warhead for covalent capture.
  • Evaluation of compounds using washout experiments to assess resistance and prolonged activation.
  • Incorporation of a trifluoroethyl group for protease protection and a C18 diacid lipid as a protractor.

Main Results:

  • Peptide analogues with covalent cross-linking capabilities demonstrated significantly increased resistance to washout, indicating prolonged GLP-1R activation.
  • The addition of a SulF cross-linkable warhead, N-terminal trifluoroethyl group, and C18 diacid lipid enhanced GLP-1's wash resistance.
  • The compound C2K26DAC18_K34SulF, featuring all three modifications, exhibited the most robust and long-lived GLP-1R agonism.

Conclusions:

  • Covalent modification of GLP-1 analogues can achieve sustained GLP-1R activation, overcoming the limitations of native GLP-1's short half-life.
  • The developed compound C2K26DAC18_K34SulF serves as a proof-of-concept for designing clinically viable long-acting GLP-1R agonists.
  • This strategy holds promise for developing novel therapeutics for metabolic disorders.