Discovery of lixisenatide analogues as long-acting hypoglycemic agents using novel peptide half-life extension technology based on mycophenolic acid

Tang, Chunli; Li, Qing; Deng, Xiaoyan; Wu, Weiwei; Liao, Lin; Liang, Kai; Huo, Rong‐Rui; Li, Chenglin; Han, Jing; Tang, Weizhong; Jiang, Neng

doi:10.1039/d0ra01002b

Cited by 4 publications

(1 citation statement)

References 54 publications

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“…36 However, a study of single-cell RNA sequencing in the brain shows that the presence of GLP-1R on BBB endothelial cells is negligible. 37 Exenatide, 38 lixisenatide, 39,40 beinaglutide, 41 liraglutide, 42 dulagutide 43 and semaglutide 44 are now commercially accessible as GLP-1 receptor agonists (Table 1). The GLP-1 receptor agonists can be classified into two groups based on their chemical structure.…”

Section: The Physiology Of the Interactions Between Glp-1ras And The ...mentioning

confidence: 99%

The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors

Dong¹,

Su²,

Zhou³

2022

DMSO

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Diabetes and obesity are growing problems worldwide and are associated with a range of acute and chronic complications, including acute myocardial infarction (AMI) and stroke. Novel anti-diabetic medications designed to treat T2DM, such as glucagonlike peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), exert beneficial effects on metabolism and the cardiovascular system. However, the underlying mechanisms are poorly understood. GLP-1RAs induce anorexic effects by inhibiting the central regulation of food intake to reduce body weight. Central/peripheral administration of GLP-1RAs inhibits food intake, accompanied by an increase in c-Fos expression in neurons within the paraventricular nucleus (PVN), amygdala, the nucleus of the solitary tract (NTS), area postrema (AP), lateral parabrachial nucleus (LPB) and arcuate nucleus (ARC), induced by the activation of GLP-1 receptors in the central nervous system (CNS). Therefore, GLP-1RAs need to pass through the blood-brain barrier to exert their pharmacological effects. In addition, studies revealed that SGLT-2is could reduce the risk of chronic heart failure in people with type 2 diabetes. SGLT-2 is extensively expressed throughout the CNS, and c-Fos expression was also observed within 2 hours of administration of SGLT-2is in mice. Recent clinical studies reported that SGLT-2is improved hypertension and atrial fibrillation by modulating the "overstimulated" renin-angiotensin-aldosterone system (RAAS) and suppressing the sympathetic nervous system (SNS) by directly/indirectly acting on the rostral ventrolateral medulla. Despite extensive research into the central mechanism of GLP-1RAs and SGLT-2is, the penetration of the blood-brain barrier (BBB) remains controversial. This review discusses the interaction between GLP-1RAs and SGLT-2is and the BBB to induce pharmacological effects via the CNS.

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Section: The Physiology Of the Interactions Between Glp-1ras And The ...mentioning

confidence: 99%

The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors

Dong¹,

Su²,

Zhou³

2022

DMSO

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Endogenous glucagon‐like peptide (GLP)‐1 as alternative for GLP‐1 receptor agonists: Could this work and how?

Smits

Holst

2023

Diabetes Metabolism Res

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In recent years, we have witnessed the many beneficial effects of glucagon‐like peptide (GLP)‐1 receptor agonists, including the reduction in cardiovascular risk in patients with type 2 diabetes, and the reduction of body weight in those with obesity. Increasing evidence suggests that these agents differ considerably from endogenous GLP‐1 when it comes to their routes of action, although their clinical effects appear to be the same. Given the limitations of the GLP‐1 receptor agonists, could it be useful to develop agents which stimulate GLP‐1 release? Here we will discuss the differences and similarities between GLP‐1 receptor agonists and endogenous GLP‐1, and will detail how endogenous GLP‐1—when stimulated appropriately—could have clinically relevant effects.

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GLP-1 and GIP receptor signaling in beta cells – A review of receptor interactions and co-stimulation

Mayendraraj

Gasbjerg

2022

Peptides

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Discovery of lixisenatide analogues as long-acting hypoglycemic agents using novel peptide half-life extension technology based on mycophenolic acid

Abstract: DiMPA albumin binders were effectively applied to lixisenatide to make 2c as a long-acting antidiabetic agent.

Cited by 4 publications

References 54 publications

The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors

The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors

Endogenous glucagon‐like peptide (GLP)‐1 as alternative for GLP‐1 receptor agonists: Could this work and how?

GLP-1 and GIP receptor signaling in beta cells – A review of receptor interactions and co-stimulation

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