Article
Biochemistry & Molecular Biology
Chunxia Liu, Chengye Li, Xingguang Cai, Yuxing Zou, Jiaxian Mo, Bin Chen, Yan Cai, Ting Han, Wenlong Huang, Hai Qian, Wenjie Zhang
Summary: GLP-1 receptor agonists have shown promising potential for treating metabolic diseases. Among them, CY-5 stands out for its strong hypoglycemic effect, ability to reduce weight gain, improve islet damage, and glucose tolerance, as well as its significant impact on NASH in mice.
BIOORGANIC CHEMISTRY
(2021)
Article
Medicine, General & Internal
Ania M. M. Jastreboff, Lee M. M. Kaplan, Juan P. P. Frias, Qiwei Wu, Yu Du, Sirel Gurbuz, Tamer Coskun, Axel Haupt, Zvonko Milicevic, Mark L. L. Hartman
Summary: Retatrutide (LY3437943), an agonist of multiple receptors, showed significant reductions in body weight in adults with obesity. The study, conducted over 48 weeks, randomized participants to receive different doses of Retatrutide or placebo, with higher doses resulting in greater weight loss.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Article
Endocrinology & Metabolism
Patrick J. Knerr, Stephanie A. Mowery, Jonathan D. Douros, Bhavesh Premdjee, Karina Rahr Hjollund, Yantao He, Ann Maria Kruse Hansen, Anette K. Olsen, Diego Perez-Tilve, Richard D. DiMarchi, Brian Finan
Summary: This study introduces empirically optimized unimolecular peptide triagonists, which effectively reduce body weight and enhance energy expenditure in DIO mice, outperforming GLP-1R mono-agonists and GLP-1R/GIPR co-agonists. The data suggest that unimolecular poly-pharmacology is an effective means to target obesity and implicate GcgR activation as a differentiating factor in incretin receptor agonists.
MOLECULAR METABOLISM
(2022)
Article
Chemistry, Medicinal
Yongliang Yuan, Zhiming Yan, Qifang Lao, Neng Jiang, Shuangmin Wu, Qinpei Lu, Jing Han, Songfeng Zhao
Summary: The development of a unimolecular triple agonist peptide targeting GLP-1, glucagon, and Y2 receptors shows great potential as a novel anti-obesity and anti-diabetic agent. This peptide, 3b, demonstrated potent activity in reducing food intake without causing nausea and had better effects on lipid metabolism, body weight, and glycemic control compared to other agonist counterparts. Targeting GLP-1R, GCGR, and Y2R with a unimolecular triple agonist peptide offers a promising route for developing new treatments for obesity and T2DM.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Endocrinology & Metabolism
Patrick J. Knerr, Stephanie A. Mowery, Jonathan D. Douros, Bhavesh Premdjee, Karina Rahr Hjollund, Yantao He, Ann Maria Kruse Hansen, Anette K. Olsen, Diego Perez-Tilve, Richard D. DiMarchi, Brian Finan
Summary: This study aims to design unimolecular peptide triagonists that activate multiple receptors to improve metabolic diseases. The optimized triagonists show promising results in controlling body weight and enhancing energy expenditure in animal models, providing a potential new approach for obesity treatment.
MOLECULAR METABOLISM
(2022)
Editorial Material
Biochemistry & Molecular Biology
Vincent Marks
Summary: The aim of this personal reminiscence is to introduce the seminal work carried out in the 1960s and 1970s that paved the way for the development of highly effective long-acting GLP-1R agonists and GLP1R/GIPR co-agonists, which are currently used in the clinical treatment of type 2 diabetes and obesity. The article highlights the contributions made by the author's collaborators Ellis Samols and Desmond Turner in understanding the nature and significance of gut glucagon-like immunoreactivity (enteroglucagon) and GIP. The identification of the potent incretin GLP-1(7-36)amide in the 1980s aligned with the earlier postulations by Samols and others in 1966 regarding the existence of a glucagon-like substance with incretin-like properties.
Article
Nutrition & Dietetics
Jiudan Zhang, Sylva Mareike Schaefer, Stefan Kabisch, Marta Csanalosi, Bettina Schuppelius, Margrit Kemper, Mariya Markova, Nina Marie Tosca Meyer, Olga Pivovarova-Ramich, Farnaz Keyhani-Nejad, Sascha Rohn, Andreas F. H. Pfeiffer
Summary: This study investigates the contribution of amino acids to postprandial hyper-glucagonemia in type 2 diabetes patients. The research shows that type 2 diabetes patients have excessive glucagon responses after mixed meals, while the obese control group only shows small initial and delayed greater glucagon responses. The role of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in mixed meals is unclear.
CLINICAL NUTRITION
(2023)
Article
Pharmacology & Pharmacy
Teng Ma, Weisheng Lu, Yongkang Wang, Peng Qian, Hong Tian, Xiangdong Gao, Wenbing Yao
Summary: The novel hybrid peptide 19W, a dual receptor agonist of GLP-1 and GIP, exhibits higher stability and improved glucose metabolism in mice and rats, leading to reduced food intake, body weight, fasting blood glucose levels, and improvements in glucose tolerance and lipid profiles. This new potential therapy shows promise in reducing adiposity, hyperglycemia, and improving liver fibrosis associated with obesity, making it a candidate for oral treatment of obesity and diabetes.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Soren Ostergaard, Johan F. Paulsson, Marina Kjaergaard Gerstenberg, Birgitte S. Wulff
Summary: The gut hormones GLP-1 and PYY3-36, when combined, have a stronger inhibitory effect on food intake compared to when they act individually. Designing a GLP-1 analogue can target both the Y-2 and GLP-1 receptors simultaneously, leading to a reduction in food intake.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Pharmacology & Pharmacy
Sonja Kinna, Myriam M. Ouberai, Silvia Sonzini, Ana L. Gomes Dos Santos, Mark E. Welland
Summary: The human peptide hormone Oxyntomodulin self-assembles into amyloid-like nanofibrils that release active, soluble Oxyntomodulin continuously in a peptide-deprived environment. The unique temperature effects on Oxyntomodulin fibril elongation kinetics and thermodynamics are characterized by optimal elongation rate at room temperature and a double-layered, triangular cross-section of the fibrils. These findings could potentially facilitate the development of pharmaceutical interventions for treating obesity and type 2 diabetes mellitus.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2021)
Article
Biochemistry & Molecular Biology
Tiago Morais, Alexandre L. L. Seabra, Barbara G. Patricio, David F. F. Carrageta, Marta Guimaraes, Mario Nora, Pedro F. F. Oliveira, Marco G. G. Alves, Mariana P. P. Monteiro
Summary: This study found that GLP-1, GIP, and glucagon have different effects on the metabolic profile of VAT depending on BMI and glycemic status. In individuals with obesity and prediabetes, GLP-1 increased alanine and lactate production and decreased isoleucine consumption, while GIP and glucagon decreased lactate and alanine production and increased pyruvate consumption.
Review
Endocrinology & Metabolism
Christophe E. M. De Block, Eveline Dirinck, Ann Verhaegen, Luc F. Van Gaal
Summary: Glucagon-like peptide-1 receptor agonists and dual GLP-1/glucose-dependent insulinotropic peptide RA tirzepatide have expanded the population of individuals reaching HbA1c and weight targets, showing potential therapeutic benefits. However, further research is needed to determine whether this will lead to improved cardiovascular outcomes and impact treatment guidelines.
DIABETES OBESITY & METABOLISM
(2022)
Article
Pharmacology & Pharmacy
Maria Buur Nordskov Gabe, Liv von Voss, Jenna Elizabeth Hunt, Sarina Gadgaard, Laerke Smidt Gasbjerg, Jens Juul Holst, Hannelouise Kissow, Bolette Hartmann, Mette Marie Rosenkilde
Summary: Biased GLP-2R agonists with modifications at the N-terminal have shown improved therapeutic effects on gut and bone growth. Variants like [F6A], [F6W], and [S7W] have less GLP-2R internalization and enhanced gut trophic actions, including increased small intestine weight, villus height, and crypt depth.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Chemistry, Medicinal
Lijing Wang
Summary: The use of incretin analogues for improving type 2 diabetes is becoming more plausible, with tirzepatide currently being the most promising option. This review explains the development of such drugs, analyzes the differences between tirzepatide and endogenous incretins, summarizes strategies for prolonging half-life, and suggests future research focusing on biased functions. The aim is to provide useful information for designing a dual glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor agonist.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2022)
Article
Endocrinology & Metabolism
Kimberley El, Jonathan D. Douros, Francis S. Willard, Aaron Novikoff, Ashot Sargsyan, Diego Perez-Tilve, David B. Wainscott, Bin Yang, Alex Chen, Donald Wothe, Callum Coupland, Mattias H. Tschoep, Brian Finan, David A. D'Alessio, Kyle W. Sloop, Timo D. Mueller, Jonathan E. Campbell
Summary: This study shows that tirzepatide, through dual activation of GLP-1R and GIPR, is highly effective in treating type 2 diabetes and obesity. It predominantly stimulates insulin secretion through GLP-1R in mouse islets, but enhances hormone secretion through both incretin receptors in human islets.
