Allosteric ligands for G protein-coupled receptors: A novel strategy with attractive therapeutic opportunities

Abstract

Allosteric receptor ligands bind to a recognition site that is distinct from the binding site of the endogenous messenger molecule. As a consequence, allosteric agents may attach to receptors that are already transmitter-bound. Ternary complex formation opens an avenue to qualitatively new drug actions at G protein-coupled receptors (GPCRs), in particular receptor subtype selective potentiation of endogenous transmitter action. Consequently, suitable exploitation of allosteric recognition sites as alternative molecular targets could pave the way to a drug discovery paradigm different from those aimed at mimicking or blocking the effects of endogenous (orthosteric) receptor activators. The number of allosteric ligands reported to modulate GPCR function is steadily increasing and some have already reached routine clinical use. This review aims at introducing into this fascinating field of drug discovery and at providing an overview about the achievements that have already been made. Various case examples will be discussed in the framework of GPCR classification (family A, B, and C receptors). In addition, the behavior at muscarinic receptors of hybrid derivatives incorporating both an allosteric and an orthosteric fragment in a common molecular skeleton will be illustrated.

Identification of Residue-to-residue Contact between a Peptide Ligand and Its G Protein-coupled Receptor Using Periodate-mediated Dihydroxyphenylalanine Cross-linking and Mass Spectrometry

“…The tridecapeptide pheromone ␣-factor analogs [DOPA 1 ]␣-factor, and [Lys 7 (BioACA)]␣-factor were done as described previously (14,22).…”

“…GPCRs are characterized by the presence of seven membrane-spanning helical segments separated by alternating intracellular and extracellular loop regions (1)(2)(3). Despite their diverse ligands, all GPCRs perform similar functions, coupling the binding of ligands to the activation of specific heterotrimeric guanine nucleotide-binding proteins (G proteins), leading to the modulation of downstream effector proteins and molecules.…”

“…Despite their diverse ligands, all GPCRs perform similar functions, coupling the binding of ligands to the activation of specific heterotrimeric guanine nucleotide-binding proteins (G proteins), leading to the modulation of downstream effector proteins and molecules. Due to their involvement in a multitude of physiological functions, GPCRs are targeted by ϳ50% of the human drugs currently marketed (1,4,5). Detailed information about GPCR-ligand interactions is critical for our understanding of GPCR-ligand binding and function.…”

Type 2 Diabetes Mellitus and Glucagon Like Peptide-1 Receptor Signalling

“…Small molecule [156]. Allosteric sites may provide novel therapeutic targets and a number of advantages compared to classical orthosteric agonists.…”

Les récepteurs couplés aux protéines G

“…D'autre part, il est à présent bien reconnu qu'un même agoniste (et a fortiori des agonistes de structures chimiques différentes) peut sélectionner des voies de signalisation intracellulaires variées dépen-dantes du contexte cellulaire ou de la réponse biologique considérée [3]. [3,4,6]. Il n'en est pas moins vrai qu'un modèle à deux états ne peut pas rendre compte de la complexité des voies de signalisation des RCPG.…”