Allosteric modulation of endogenous metabolites as an avenue for drug discovery
Research output: Contribution to journal › Article › Research › peer-review
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and a key drug target class. Recently, allosteric drugs that can co-bind with, and modulate the activity of, the endogenous ligand(s)for the receptor have become a major focus of the pharmaceutical and biotechnology industry for the development of novel GPCR therapeutics. This class of drugs has distinct properties when compared to drugs targeting the endogenous(orthosteric)ligand binding site that include the ability to sculpt cellular signalling, and to respond differently in the presence of discrete orthosteric ligands; a behaviour termed probe dependence . Here, using cell signalling assays combined with ex vivo and in vivo studies of insulin secretion, we demonstrate that allosteric ligands can cause marked potentiation of previously inert metabolic products of neurotransmitters and peptide hormones, a novel consequence of the phenomenon of probe dependence. Indeed, at the muscarinic M(2) receptor and glucagon-like peptide-1 receptor, allosteric potentiation of the metabolites, choline and GLP-1(9-36)NH(2), respectively, was 100-fold and up to 200-fold greater than that seen with the physiological signalling molecules acetylcholine and GLP-1(7-36)NH(2). Modulation of GLP-1(9-36)NH(2) was also demonstrated in ex vivo and in vivo assays of insulin secretion.This work opens up new avenues for allosteric drug discovery by directly targeting modulation of metabolites, but it also identifies a behaviour that could contribute to unexpected clinical outcomes if interaction of allosteric drugs with metabolites is not part of their preclinical assessment.