Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors

Zhao, Fuqiang; Zhou, Qingtong; Cong, Zhaotong; Hang, Kaini; Zou, Xinyu; Zhang, Chao; Chen, Yan; Dai, Antao; Liang, Anyi; Ming, Qianqian; Wang, Mu; Chen, Li-Nan; Xu, Peiyu; Chang, Rulve; Feng, Wenbo; Xia, Tian; Zhang, Yan; Wu, Beili; Yang, Dehua; Zhao, Lihua; Xu, H. Eric; Wang, Mingwei

doi:10.1038/s41467-022-28683-0

Cited by 63 publications

(76 citation statements)

References 66 publications

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“…Elucidating the impact of genetic variations on the GIP endogenous system ( 88 ), accompanied by structural insights into the peptide bound GIPR ( 57 , 89 ), can provide valuable information for future drug discovery efforts. This is highlighted by the fact that both agonists and antagonists at the GIPR could provide valuable modes of action in the treatment of T2D and obesity ( 90 ).…”

Section: Discussionmentioning

confidence: 99%

The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection

et al. 2022

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The intestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is involved in important physiological functions, including postprandial blood glucose homeostasis, bone remodeling, and lipid metabolism. While mutations leading to physiological changes can be identified in large-scale sequencing, no systematic investigation of GIP missense variants has been performed. Here, we identified 168 naturally occurring missense variants in the human GIP genes from three independent cohorts comprising ~720,000 individuals. We examined amino acid changing variants scattered across the pre-pro-GIP peptide using in silico effect predictions, which revealed that the sequence of the fully processed GIP hormone is more protected against mutations than the rest of the precursor protein. Thus, we observed a highly species-orthologous and population-specific conservation of the GIP peptide sequence, suggestive of evolutionary constraints to preserve the GIP peptide sequence. Elucidating the mutational landscape of GIP variants and how they affect the structural and functional architecture of GIP can aid future biological characterization and clinical translation.

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Section: Discussionmentioning

confidence: 99%

The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection

et al. 2022

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“…In addition, hepatoprotection cannot be overlooked [45]. The structural basis of tirzepatide in terms of its functional versatility has been reported [46], and its physiological mechanisms in T2D described [47]. In the human clinical trial (NCT03951753), tirzepatide was compared to semaglutide and placebo with respect to T2D patients' responses to blood sugar levels after a meal over 28 weeks.…”

Section: Structure and Activitymentioning

confidence: 99%

Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review

Chavda¹,

Ajabiya

Teli

et al. 2022

Molecules

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The prevalence of obesity and diabetes is an increasing global problem, especially in developed countries, and is referred to as the twin epidemics. As such, advanced treatment approaches are needed. Tirzepatide, known as a ‘twincretin’, is a ‘first-in-class’ and the only dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonist, that can significantly reduce glycemic levels and improve insulin sensitivity, as well as reducing body weight by more than 20% and improving lipid metabolism. This novel anti-diabetic drug is a synthetic peptide analog of the human GIP hormone with a C20 fatty-diacid portion attached which, via acylation technology, can bind to albumin in order to provide a dose of the drug, by means of subcutaneous injection, once a week, which is appropriate to its a half-life of about five days. Tirzepatide, developed by Eli Lilly, was approved, under the brand name Mounjaro, by the United States Food and Drug Administration in May 2022. This started the ‘twincretin’ era of enormously important and appealing dual therapeutic options for diabetes and obesity, as well as advanced management of closely related cardiometabolic settings, which constitute the leading cause of morbidity, disability, and mortality worldwide. Herein, we present the key characteristics of tirzepatide in terms of synthesis, structure, and activity, bearing in mind its advantages and shortcomings. Furthermore, we briefly trace the evolution of this kind of medical agent and discuss the development of clinical studies.

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“…A 20-carbon fatty acid linked to the lysine residue in position 20 of the primary structure allows TZP to be bound to circulating albumin. Acylation technology, previously adopted and developed for Liraglutide and Semaglutide, increases TZP half-life to around five days, making it administrable once weekly (28,(31)(32)(33).…”

Section: Dual Gip and Glp-1 Receptor Agonist: Focus On Tirzepatidementioning

confidence: 99%

Basal insulin intensification with GLP-1RA and dual GIP and GLP-1RA in patients with uncontrolled type 2 diabetes mellitus: A rapid review of randomized controlled trials and meta-analysis

Lisco

Tullio²,

Disoteo³

et al. 2022

Front. Endocrinol.

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Tirzepatide, a dual agonist of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide 1 (GLP-1) receptors, improved glucose control and reduced body weight in different therapeutic approaches. Herein, we overviewed the role of GIP and GLP-1 in the pathophysiology of type 2 diabetes and systematically reviewed the efficacy and safety of injectable incretin-based therapy added to basal insulin in light of the results of the SURPASS-5 trial. We identified eleven randomized clinical trials. GLP-1 receptor agonists (GLP-1RAs) or Tirzepatide added to basal insulin than rigorously titrated basal insulin significantly ameliorates glucose control (Δ HbA1c = -1%, 95% CI -1.25; -0.74, I2 94%; Δ FPG = -14.6 mg/dL, 95% CI -21.6-; -7.6, I2 90%; chance to achieve HbA1c <7% = RR 2.62, 95% CI 2.10; 3.26, I2 89%), reduces body weight (Δ = -3.95 kg, 95% CI -5.1, -2.79, I2 96%) without increasing the risk of hypoglycemia (RR = 1.01, 95% CI 0.86; 1.18, I2 7.7%). Tirzepatide provides an impressive weight loss exceeding that observed with GLP-1RAs. Injectable incretin-based therapy plus basal insulin remains a potent and safe therapeutic approach in uncontrolled type 2 diabetes patients previously treated with basal insulin alone. Tirzepatide is expected to ameliorate the management of “diabesity” in this usually difficult-to-treat cluster of patients.

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Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors

Cited by 63 publications

References 66 publications

The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection

The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection

Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review

Basal insulin intensification with GLP-1RA and dual GIP and GLP-1RA in patients with uncontrolled type 2 diabetes mellitus: A rapid review of randomized controlled trials and meta-analysis

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