title: Allosteric modulation of endogenous metabolites as an avenue for drug discovery.
abstract: 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 therapeutic agents. This class of drugs has distinct properties compared with drugs targeting the endogenous (orthosteric) ligand-binding site that include the ability to sculpt cellular signaling and to respond differently in the presence of discrete orthosteric ligands, a behavior termed "probe dependence." Here, using cell signaling 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 (GLP-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 signaling 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 behavior that could contribute to unexpected clinical outcomes if interaction of allosteric drugs with metabolites is not part of their preclinical assessment.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Denise
authors.initials: D
authors.lastname: Wootten
authors.forename: Emilia E
authors.initials: EE
authors.lastname: Savage
authors.forename: Celine
authors.initials: C
authors.lastname: Valant
authors.forename: Lauren T
authors.initials: LT
authors.lastname: May
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Sloop
authors.forename: James
authors.initials: J
authors.lastname: Ficorilli
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Showalter
authors.forename: Francis S
authors.initials: FS
authors.lastname: Willard
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D036361:Peptide Hormones / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D036361:Peptide Hormones; D004364:Pharmaceutical Preparations; D043562:Receptors, G-Protein-Coupled