Article ; Online: G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype?
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
2024 Volume 172, Page(s) 116245
Abstract: Globesity' is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like- ...
| Abstract | 'Globesity' is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like-peptide-1 (GLP-1) has been highly captivated during the last decade owing to its multisystemic pleiotropic clinical outcomes beyond inherent glucoregulatory action. That fostered a pharmaceutical interest in synthetic GLP-1 analogues to tackle type-2 diabetes (T2D), obesity and related complications. Besides, mechanistic insights on metabolic surgeries allude to an incretin-based hormonal combination strategy for weight loss that emerged as a forerunner for the discovery of injectable 'unimolecular poly-incretin-agonist' therapies. Physiologically, intestinal enteroendocrine L-cells (EECs) are the prominent endogenous source of GLP-1 peptide. Despite comprehending the potential of various G protein-coupled receptors (GPCRs) to stimulate endogenous GLP-1 secretion, decades of translational GPCR research have failed to yield regulatory-approved endogenous GLP-1 secretagogue oral therapy. Lately, a dual/poly-GPCR agonism strategy has emerged as an alternative approach to the traditional mono-GPCR concept. This review aims to gain a comprehensive understanding by revisiting the pharmacology of a few potential GPCR-based complementary avenues that have drawn attention to the design of orally active poly-GPCR agonist therapy. The merits, challenges and recent developments that may aid future poly-GPCR drug discovery are critically discussed. Subsequently, we project the mechanism-based therapeutic potential and limitations of oral poly-GPCR agonism strategy to augment intestinal GLP-1 for weight loss. We further extend our discussion to compare the poly-GPCR agonism approach over invasive surgical and injectable GLP-1-based regimens currently in clinical practice for obesity. |
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| MeSH term(s) | Humans ; Glucagon-Like Peptide 1 ; Incretins ; Obesity/drug therapy ; Receptors, G-Protein-Coupled ; Weight Loss ; Peptides |
| Chemical Substances | Glucagon-Like Peptide 1 (89750-14-1) ; Incretins ; Receptors, G-Protein-Coupled ; Peptides |
| Language | English |
| Publishing date | 2024-02-09 |
| Publishing country | France |
| Document type | Journal Article ; Review |
| ZDB-ID | 392415-4 |
| ISSN | 1950-6007 ; 0753-3322 ; 0300-0893 |
| ISSN (online) | 1950-6007 |
| ISSN | 0753-3322 ; 0300-0893 |
| DOI | 10.1016/j.biopha.2024.116245 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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