Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines DOI Creative Commons
Wen‐Jing Xiao, Wenjie Jiang, Zheng Chen

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 5, 2025

The successful approval of peptide-based drugs can be attributed to a collaborative effort across multiple disciplines. integration novel drug design and synthesis techniques, display library technology, delivery systems, bioengineering advancements, artificial intelligence have significantly expedited the development groundbreaking drugs, effectively addressing obstacles associated with their character, such as rapid clearance degradation, necessitating subcutaneous injection leading increasing patient discomfort, ultimately advancing translational research efforts. Peptides are presently employed in management diagnosis diverse array medical conditions, diabetes mellitus, weight loss, oncology, rare diseases, additionally garnering interest facilitating targeted platforms advancement vaccines. This paper provides an overview present market clinical trial progress therapeutics, platforms, It examines key areas through literature analysis emphasizes structural modification principles well recent advancements screening, design, technologies. accelerated including peptide-drug complexes, new vaccines, innovative diagnostic reagents, has potential promote era precise customization disease therapeutic schedule.

Language: Английский

A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings DOI Creative Commons
Murielle M. Véniant,

Shu-Chen Lu,

Larissa Atangan

et al.

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(2), P. 290 - 303

Published: Feb. 5, 2024

Abstract Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate through their receptors (R). AMG 133 (maridebart cafraglutide) bispecific molecule engineered by conjugating fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist using amino acid linkers. Here, we confirm the GLP-1R activities in cell-based systems report ability of reduce body improve metabolic markers male obese mice cynomolgus monkeys. In phase 1, randomized, double-blind, placebo-controlled study participants with obesity ( NCT04478708 ), had an acceptable safety tolerability profile along pronounced dose-dependent multiple ascending dose cohorts, loss was maintained up 150 days after last dose. These findings support continued evaluation 133.

Language: Английский

Citations

71
The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets DOI Creative Commons
Kimberley El, Jonathan D. Douros, Francis S. Willard

et al.

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(6), P. 945 - 954

Published: June 5, 2023

Abstract The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake facilitate glucose tolerance . GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes obesity 2 , whereas therapeutic potential GIP (GIPR) a subject debate. Tirzepatide agonist at both GIPR GLP-1R highly effective type 3,4 However, although tirzepatide activates in cell lines mouse models, it not clear whether or how dual agonism contributes its benefit. Islet beta cells express GIPR, secretion mechanism by which incretin agonists improve glycemic control 5 Here, we show islets, stimulates predominantly through GLP-1R, owing reduced potency GIPR. human antagonizing activity consistently decreases response tirzepatide. Moreover, enhances glucagon somatostatin islets. These data demonstrate islet hormone from islets receptors.

Language: Английский

Citations

66
Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial DOI Creative Commons
Arun J. Sanyal, Lee M. Kaplan, Juan P. Frías

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(7), P. 2037 - 2048

Published: June 10, 2024

Abstract Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions 22.8% 24.2% with retatrutide 8 12 mg, respectively. The primary objective this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks participants that metabolic dysfunction-associated steatotic disease ≥10% LF. Here, randomized, double-blind, placebo-controlled trial, ( n = 98) were randomly assigned 48 once-weekly subcutaneous (1, 4, or mg dose) placebo. LF −42.9% (1 mg), −57.0% (4 −81.4% (8 −82.4% (12 mg) +0.3% (placebo) (all P < 0.001 versus placebo). At weeks, normal (<5%) achieved by 27% 52% 79% 86% 0% participants. significantly related changes body weight, abdominal measures associated improved insulin sensitivity lipid metabolism. ClinicalTrials.gov registration NCT04881760 .

Language: Английский

Citations

60
Gut hormone co-agonists for the treatment of obesity: from bench to bedside DOI
Rubén Nogueiras, Michael A. Nauck,

Matthias H. Tschöp

et al.

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(6), P. 933 - 944

Published: June 12, 2023

Language: Английский

Citations

59
GIPR/GLP-1R dual agonist therapies for diabetes and weight loss—chemistry, physiology, and clinical applications DOI Creative Commons
Jonathan E. Campbell, Timo D. Müller, Brian Finan

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(9), P. 1519 - 1529

Published: Aug. 16, 2023

Language: Английский

Citations

58
Gut hormone-based pharmacology: novel formulations and future possibilities for metabolic disease therapy DOI Creative Commons

Matthias H. Tschöp,

Rubén Nogueiras, Bo Åhrén

et al.

Diabetologia, Journal Year: 2023, Volume and Issue: 66(10), P. 1796 - 1808

Published: May 20, 2023

Abstract Glucagon-like peptide-1 (GLP-1) receptor agonists are established pharmaceutical therapies for the treatment of type 2 diabetes and obesity. They mimic action GLP-1 to reduce glucose levels through stimulation insulin secretion inhibition glucagon secretion. also body weight by inducing satiety central actions. The used clinically based on exendin-4 native available as formulations daily or weekly s.c. oral administration. agonism is achieved inhibitors dipeptidyl peptidase-4 (DPP-4), which prevent inactivation glucose-dependent insulinotropic polypeptide (GIP), thereby prolonging their raised after meal ingestion. Other developments in include formation small orally compounds with potential pharmaceutically stimulate from gut. In addition, GLP-1/glucagon GLP-1/GIP dual GLP-1/GIP/glucagon triple have shown blood effects islets peripheral tissues, improving beta cell function stimulating energy expenditure. This review summarises gut hormone-based presents future outlook use Graphical

Language: Английский

Citations

51
100 years of glucagon and 100 more DOI Open Access
Nicolai J. Wewer Albrechtsen, Jens J. Holst, Alan D. Cherrington

et al.

Diabetologia, Journal Year: 2023, Volume and Issue: 66(8), P. 1378 - 1394

Published: June 27, 2023

Language: Английский

Citations

51
G Protein-Coupled Receptors: A Century of Research and Discovery DOI

Samuel Liu,

Preston J. Anderson, Sudarshan Rajagopal

et al.

Circulation Research, Journal Year: 2024, Volume and Issue: 135(1), P. 174 - 197

Published: June 20, 2024

GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in human genome, with ≈800 members. regulate nearly every aspect of physiology and disease, thus serving important drug targets cardiovascular disease. Sharing a conserved structure comprised α-helices, couple to heterotrimeric G-proteins, GPCR kinases, β-arrestins, promoting downstream signaling through second messengers other intracellular pathways. development has led therapies, such antagonists β-adrenergic angiotensin II receptors for heart failure hypertension, agonists glucagon-like peptide-1 reducing adverse events emerging indications. There continues be major interest cardiometabolic driven by advances mechanistic studies structure-based design. This review recounts rich history research, including current state clinically used drugs, highlights newly discovered aspects biology promising directions future investigation. As additional mechanisms regulating uncovered, new strategies targeting these ubiquitous hold tremendous promise field medicine.

Language: Английский

Citations

37
A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity DOI
Manmeet Kaur, Saurav Misra

European Journal of Clinical Pharmacology, Journal Year: 2024, Volume and Issue: 80(5), P. 669 - 676

Published: Feb. 17, 2024

Language: Английский

Citations

32
Unleashing the power of retatrutide: A possible triumph over obesity and overweight: A correspondence DOI Creative Commons
Muhammad Naeem, Laiba Imran, Umm E. Salma Shabbar Banatwala

et al.

Health Science Reports, Journal Year: 2024, Volume and Issue: 7(2)

Published: Feb. 1, 2024

Abstract Background and Aims Overweight obesity have become global health challenges with increasing prevalence. Several drugs received Food Drug Administration approval for nonsyndromic treatment, but most limitations, including gastrointestinal side effects limited weight loss efficacy. Body Retatrutide, a novel incretin mimetic agent, has shown promise in clinical trials significant reduction. It demonstrated dosage‐dependent pharmacokinetics favorable safety profiles. The primary focus of this paper is to explore retatrutide critically assess its justify use feasibility while highlighting shortcomings. This also delves into the subject manifestations. Conclusion expected that retatrutide, triple agonist, will result among individuals who are obese or overweight.

Language: Английский

Citations

24