G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype?

Mohan Patil; Ilaria Casari; Leon N. Warne; Marco Falasca

doi:10.1016/j.biopha.2024.116245

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G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype?

Journal article

Open access

Peer reviewed

G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype?

Mohan Patil, Ilaria Casari, Leon N. Warne and Marco Falasca

Biomedicine & pharmacotherapy, Vol.172, 116245

2024

DOI: https://doi.org/10.1016/j.biopha.2024.116245

PMID: 38340396

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Abstract

Intestinal GLP-1

G-protein coupled receptors (GPCRs)

Weight-loss

Oral poly-GPCR agonist

GLP-1-based injectable dual/poly peptide analogues

Metabolic surgery

‘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.

Details

Title: G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype?
Authors/Creators: Mohan Patil - Curtin University
Ilaria Casari - Curtin University
Leon N. Warne - Little Green Pharma, West Perth, Western Australia 6872, Australia
Marco Falasca - University of Parma
Publication Details: Biomedicine & pharmacotherapy, Vol.172, 116245
Publisher: Elsevier Masson SAS
Identifiers: 991005638973607891
Murdoch Affiliation: School of Veterinary Medicine
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.26 Diabetes; 1.26.831 GLP-1
Web Of Science research areas: Medicine, Research & Experimental; Pharmacology & Pharmacy
ESI research areas: Pharmacology & Toxicology