GPCR drug discovery: new agents, targets and indications

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

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Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretionin vitroandin vivoof a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss type 2 diabetes (T2D) patients. Agonists which bind stimulate multiple receptors have shown particular promise. However, off target effects, including nausea diarrhoea, remain a complication using these agents, modified versions with optimized pharmacological profiles and/or biased signaling at the cognate are increasingly sought. Here, we describe synthesis properties molecule binds glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) (GLP-1R GIPR) enhance secretion. HISHS-2001 shows increased affinity GLP-1R, well tendency towards reduced internalization recycling this receptor versus FDA-approved dual GLP-1R/GIPR agonist tirzepatide. also displayed significantly greater bias cAMP generation β-arrestin recruitment compared In contrast, G αs was lower tirzepatide but higher GIPR. Administered obese hyperglycaemic db/db mice, circulating whilst lowering body HbA1c similar efficacy substantially doses. Thus, represents novel improved profile.

Language: Английский

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Glucagon-like peptide-1 receptor agonism and end-organ protection

Trends in Endocrinology and Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Identification of exendin-4 (a glucagon-like peptide 1 receptor agonist, GLP-1RA) in Gila monster venom may be regarded as one the most serendipitous discoveries recent times. GLP-1RAs are now an established therapeutic approach type 2 diabetes (T2D), body weight management, and cardiovascular (CV) risk protection. Furthermore, there is a growing platform evidence that GLP-1RA has extended benefit renal, hepatic, respiratory, neurological diseases. One can speculate on biological advantage to monster, but for humankind peptides with significant potential improve disease-related outcomes. We report latest mechanisms GLP-1RA-mediated end-organ protection uniquely highlight its future development across multiple disease areas.

Language: Английский

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Future Perspectives in the Management of Obesity

Published: Jan. 1, 2025

Language: Английский

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Dual and Triple Gut Peptide Agonists on the Horizon for the Treatment of Type 2 Diabetes and Obesity. An Overview of Preclinical and Clinical Data

Current Obesity Reports, Journal Year: 2025, Volume and Issue: 14(1)

Published: April 11, 2025

Abstract Purpose of Review The development long-acting incretin receptor agonists represents a significant advance in the fight against concurrent epidemics type 2 diabetes mellitus (T2DM) and obesity. aim present review is to examine cellular processes underlying actions these new, highly classes peptide agonists. We further explore potential multi-agonist drugs as well mechanisms through which gut-brain communication can be used achieve long-term weight loss without negative side effects. Recent Findings Several unimolecular dual-receptor have shown promising clinical efficacy studies when alone or conjunction with approved glucose-lowering medications. also describe incretin-based pharmacotherapy, starting exendin- 4 ending identification multi-incretin hormone agonists, appear next major step T2DM discuss multi-agonists currently trials how each new generation improves their effectiveness. Since most glucose-dependent insulinotropic polypeptide (GIP) receptor: glucagon-like peptide- 1 (GLP- 1) glucagon triagonists compete bariatric surgery, success agents preclinical models suggests bright future for treatment metabolic diseases. To fully understand treatments affect body weight, research needed.

Language: Английский

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Inkretine als Grundlage der Adipositastherapie

Deleted Journal, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

Obesity represents an immense challenge for patients and physicians due to its numerous comorbidities complications. For a long time, safe effective pharmacological treatment remained wishful thinking. Bariatric surgery was considered the only option sustained weight loss; however, with advent of incretin-based treatment, initially introduced as highly component anti-diabetic research began focus on complex gastroenteropancreatic endocrine system, including central hunger satiety regulation. This shift driven by discovery remarkable side effect: placebo-controlled reduction. Subsequent groundbreaking developments based long-acting peptides, administration which could be reduced from twice daily in earlier forms once weekly, now enables significant reduction over 20%, tolerable safety profile. article provides illustrative overview corresponding associations highlights this milestone obesity treatment.

Language: Английский

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Trends in Utilization of Glucose- and Weight-Lowering Medications After Tirzepatide Approval in the United States

Annals of Internal Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

Recent trends in use of tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonist (RA), versus other glucose-lowering medications (GLMs) weight-lowering (WLMs) remain unexplored. To describe insurance claims for GLMs WLMs after tirzepatide approval. Population-based cohort study. Claims data from large U.S. commercial database (January 2021 to December 2023). Adults (aged ≥18 years) with type 2 diabetes (T2D) without dispensations WLMs. Any was defined as medication dispensation regardless prior use. Incident the preceding year. Monthly before market entry. Tirzepatide uptake additionally compared initial postapproval increased markedly among adults T2D prescribed GLMs, reaching 12.3% all GLM by 2023. Similar patterns were observed sodium-glucose cotransporter-2 inhibitors (14.5% 24.4%) GLP-1 RAs (19.5% 28.5%). Dispensations including metformin, declined. Among but WLMs, (0.0% 40.6%) semaglutide (2.4 mg) 32.2%) sharply, (2.0 most frequently dispensed WLM, increasing 37.8% 45.7%. incident users. more rapid sustained periods medications. Generalizability health is uncertain. These findings highlight sharp entry enhance understanding rapidly shifting landscape prescribing National Institute Diabetes Digestive Kidney Diseases.

Language: Английский

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Overweight and Obesity in Adults with Type 1 Diabetes: A Growing Challenge

Diabetology, Journal Year: 2024, Volume and Issue: 5(3), P. 234 - 245

Published: June 24, 2024

The prevalence of obesity in adults with type 1 diabetes is increasing and reflects the rates general adult population. coexistence overweight or poses a major challenge to effective glycemic weight management. In addition, individuals living T1D are at greater cardiometabolic risk more prone develop chronic complications comparison normal diabetes. Although represents growing population, awareness this issue still low. This review provides summary current data on trends, causes, strategies, challenges managing

Language: Английский

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Regulation of GLP-1 and Glucagon Receptor Function by β-Arrestins in Metabolically Important Cell Types

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) are polypeptides derived from a common precursor (preproglucagon) that modulates the activity of numerous cell types involved in regulating glucose energy homeostasis. GLP-1 GCG exert their biological functions via binding to specific G protein-coupled receptors (GLP-1Rs GCGRs). Ligand-activated GLP-1Rs GCGRs preferentially activate heterotrimeric protein Gs, resulting increased cytosolic cAMP levels. However, activation two also leads recruitment β-arrestin-1 -2 (βarr1 βarr2, respectively) intracellular surface receptor proteins. The β-arrestins activated contributes termination receptor-stimulated coupling. In addition, receptor-β-arrestin complexes can act as signaling nodes own right by modulating many pathways. this Review, we will discuss roles βarr1 βarr2 key metabolic mediated GCGRs. During past decade, GLP-1R agonists have emerged highly efficacious antidiabetic antiobesity drugs. Moreover, dual stimulate both predicted offer additional therapeutic benefits compared agonist monotherapy. We summarize try synthesize series studies suggesting development protein-biased and/or GCGR agonists, which do not lead β-arrestins, may even more agents.

Language: Английский

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The safety, tolerability, pharmacokinetics and pharmacodynamics of GZR18 in healthy American and Chinese adult subjects

Diabetes Obesity and Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Abstract Aims GZR18, a novel long‐acting GLP‐1 receptor agonist, has demonstrated substantial metabolic improvements in diabetic and obese animal models. The present studies aimed to evaluate the safety, tolerability, pharmacokinetics (PK) pharmacodynamics (PD) of ascending dose GZR18 healthy American Chinese subjects. Materials Methods In these phases 1, randomized, double‐blind, placebo‐controlled, sequential, dose‐escalation US studies, adults with similar age were enrolled once‐weekly subcutaneous injection or placebo. included three cohorts male subjects (cohorts US‐1–3) six CN‐1–6, female), each specified target ranging from 1 50 μg/kg (1–10 for study 5–50 study). primary endpoints safety tolerability GZR18. Blood samples collected PK PD analysis before after dosing. A population was conducted ascertain whether there are ethnic differences between adults. Results exposure comparable subjects, geometric mean ratio two populations AUC 0‐t C max close 1. dose‐dependent increase 0–t occurred both populations. median time maximum plasma concentrations ( T ) ranged 72 96 h, 60 h half‐life approximately 7 days Evident body weight reduction observed treatment groups CN‐3–6 on Day 15, −1.25 −1.86 kg; −1.88% −3.11%). No deaths, serious adverse events hypoglycaemia reported. Decreased appetite nausea most frequently reported treatment‐emergent events, mild severity. profile generally consistent same class drugs. Conclusions demonstrates good profiles support its further clinical evaluation glycaemic control.

Language: Английский

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