Point-Substitution of Phenylalanine Residues of 26RFa Neuropeptide: A Structure-Activity Relationship Study

Lefranc, Benjamin; Alim, Karima; Neveu, Cindy; Marec, Olivier Le; Dubessy, Christophe; Boutin, Jean A.; Chuquet, Julien; Vaudry, David; Prévost, Gaëtan; Picot, Marie Christine; Vaudry, Hubert; Chartrel, Nicolas; Leprince, Jérôme

doi:10.3390/molecules26144312

Cited by 2 publications

(1 citation statement)

References 57 publications

(367 reference statements)

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“…It could also suggest that a reasonable modification of the sequence could have negligible impact on the agonist activity and that therefore, designing a peptide antagonist from a peptide agonist is a complicated task. Many examples support this remark; let us mention, among others, the more than 300 analogues of 26RFa that we have synthesized without finding the slightest antagonist [58][59][60][61][62].…”

Section: Finding Synthetic Agonists For Peptidergic Receptors: the Ca...mentioning

confidence: 64%

Why Search for Alternative GPCR Agonists?

Boutin

Leprince

2023

Receptors

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Intuitively, it is easy to understand why we search for G protein-coupled receptor (GPCR) antagonists. It is obviously to block a functionality of a specific receptor potentially linked to some aspects of disease. Whether by focused research or by serendipity, many drugs were discovered in the last century that function as antagonist at a precise receptor. A current idea is that at least half of the drugs on the market are antagonist ligands of GPCRs. Then, why are we searching for alternative receptor agonists while the endogenous activating molecule is known? In the present commentary we try to rationalize these fields of research, since they proved to be very successful over the years, with receptor pharmacology populated with dozens of alternative agonists, particularly to bioaminergic receptors, and to a lesser extent to peptidergic ones. However, the action of such compounds is not well-characterized: are they surrogates to the endogenous agonist, and if yes in which context and for which purpose? The present essay is a reflection on this subject that leads to fundamental interrogations of our understanding of GPCR roles and functions.

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Section: Finding Synthetic Agonists For Peptidergic Receptors: the Ca...mentioning

confidence: 64%

Why Search for Alternative GPCR Agonists?

Boutin

Leprince

2023

Receptors

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The 26RFa (QRFP)/GPR103 Neuropeptidergic System: A Key Regulator of Energy and Glucose Metabolism

Devère,

Takhlidjt,

Prévost

et al. 2024

Neuroendocrinology

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Background: Obesity and type 2 diabetes are strongly associated pathologies, currently considered as a worldwide epidemic problem. Understanding the mechanisms that drive the development of these diseases would enable to develop new therapeutic strategies for their prevention and treatment. Particularly, the role of the brain in the energy and glucose homeostasis has been studied for two decades. In specific, the hypothalamus contains well-identified neural networks regulating appetite and potentially also glucose homeostasis. A new concept has thus emerged, suggesting that obesity and diabetes could be due to a dysfunction of the same, still poorly understood, neural networks. Summary: The neuropeptide 26RFa (also termed QRFP) belongs to the family of RFamide regulatory peptides and has been identified as the endogenous ligand of the human G protein-coupled receptor GPR103 (QRFPR). The primary structure of 26RFa is strongly conserved during vertebrate evolution, suggesting its crucial roles in the control of vital functions. Indeed, the 26RFa/GPR103 peptidergic system is reported to be involved in the control of various neuroendocrine functions, notably the control of energy metabolism in which it plays an important role, both centrally and peripherally, since 26RFa regulates feeding behavior, thermogenesis and lipogenesis. Moreover, 26RFa is reported to control glucose homeostasis both peripherally, where it acts as an incretin, and centrally, where the 26RFa/GPR103 system relays insulin signaling in the brain to control glucose metabolism. Key Messages: This review gives a comprehensive overview of the role of the 26RFa/GPR103 system as a key player in the control of energy and glucose metabolism. In pathophysiological context, this neuropeptidergic system represents a prime therapeutic target whose mechanisms are highly relevant to decipher.

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Point-Substitution of Phenylalanine Residues of 26RFa Neuropeptide: A Structure-Activity Relationship Study

Cited by 2 publications

References 57 publications

Why Search for Alternative GPCR Agonists?

Why Search for Alternative GPCR Agonists?

The 26RFa (QRFP)/GPR103 Neuropeptidergic System: A Key Regulator of Energy and Glucose Metabolism

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