Glucagon‐Like Peptide‐1 (GLP‐1)‐Based Therapeutics: Current Status and Future Opportunities beyond Type 2 Diabetes

Abstract

Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L-cells following food intake, and plays an important role in glucose homeostasis due to its stimulation of glucose-dependent insulin secretion. Further, GLP-1 is also associated with protective effects on pancreatic β-cells and the cardiovascular system, decreased appetite, and weight loss, making GLP-1 derivatives an exciting treatment for type 2 diabetes and obesity. Despite these benefits, wild-type GLP-1 exhibits a short circulation time due to its poor metabolic stability and rapid renal clearance, and must be administered by injection, making it a poor therapeutic agent. Many strategies have been used to improve the circulation time of GLP-1 (e.g., mutations, unnatural amino acids, depot formulations, use of exendin-4 sequences, and fusions with high-molecular-weight proteins or polymers), with its therapeutic utility further improved by adding agonist activity for gastric inhibitory peptide and glucagon receptors. This minireview focuses on strategies that have been used to improve the pharmacokinetics of GLP-1 and provides an overview of GLP-1-based therapeutics in the pipeline.

Ureidopeptide GLP-1 analogues with prolonged activity in vivo via signal bias and altered receptor trafficking

“…Lixisenatide is a once daily GLP-1R agonist with an increased binding affinity to the receptor and a prolonged half-life in vivo compared to exenatide. 11 In this case, Lixi L (13) shows a small glucose-lowering effect 9 hours aer treatment, compared to the vehicle. In contrast, 11 and 14 demonstrated a strong ability to control blood glucose levels with almost no increase in the IPGTT curves.…”

“…9 One particular problem with the use of native GLP-1, a 29 amino acid natural peptide hormone, is its short in vivo half-life of 2-3 min. 10 Many modications have therefore been developed to prolong the GLP-1 lasting period, notably, sequence remodelling and extension (exenatide and lixisenatide), 11 fatty acid acylation to promote binding to plasma albumin (liraglutide and semaglutide), 11 bonding or fusion to large proteins (dulaglutide, albiglutide, and efpeglenatide), 11 non-natural amino acid replacements, 12 side chain cross linking, 13 and more recently a / b-residue replacements, 14 thioamide, 15 and peptide-oligourea hybrids 16 (Fig. 1).…”

“…Gly) to prevent proteolytic cleavage by DPP-4. 10,11 However, despite having a glycine in position 2, exenatide, an FDA approved once-weekly treatment for T2DM, is still susceptible to degradation at its Nterminus. 17 We therefore hypothesize that modifying the backbone of exenatide might improve its proteolytic stability and prolong its activity in vivo.…”

A free‐energy landscape for the glucagon‐like peptide 1 receptor GLP1R

“…All these effects contribute to better management of the pathophysiology of diabetes and obesity. [18][19][20] Broadly, GPCRs are membrane-bound proteins that partake in diverse physiological processes (eg, hormonal regulation, cognition, mood, smell, and taste 21 ), conveying information and allowing cells to react to their environment. GPCRs are omnipresent in human physiology, 22 and their malfunction causes and affects a variety of malignant and nonmalignant disorders including various cancers, 23 diabetes, 24 Alzheimer's disease, 25 and more.…”

“…30,31 GLP1R agonists (GLP1RAs), such as semaglutide and liraglutide, are increasingly used to treat diabetic patients, 32,33 exhibiting benefits such as reducing the risk of death from heart diseases in diabetic patients 32 ; having insulinotropic effects in type 1 diabetes patients 34 ; and are known to increase the growth, differentiation, and regeneration of β cells. 18,35 Overall, GLP1RAs-related studies show promise against type 1 and type 2 diabetes, prediabetes, obesity, as well as heart, liver, and neurological diseases. 19,36 And yet, investigating GLP1R from a structural perspective has been surprisingly limited.…”