Allosteric modulation of endogenous metabolites as an avenue for drug discovery

Denise L Wootten, Emilia Elizabeth Savage, Celine Valant, Lauren T May, Kyle W Sloop, James Ficorilli, Aaron D Showalter, Francis S Willard, Arthur Christopoulos, Patrick M Sexton

Research output: Contribution to journalArticleResearchpeer-review

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 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.
Original languageEnglish
Pages (from-to)281 - 290
Number of pages10
JournalMolecular Pharmacology
Volume82
Issue number2
DOIs
Publication statusPublished - 2012

Cite this

Wootten, Denise L ; Savage, Emilia Elizabeth ; Valant, Celine ; May, Lauren T ; Sloop, Kyle W ; Ficorilli, James ; Showalter, Aaron D ; Willard, Francis S ; Christopoulos, Arthur ; Sexton, Patrick M. / Allosteric modulation of endogenous metabolites as an avenue for drug discovery. In: Molecular Pharmacology. 2012 ; Vol. 82, No. 2. pp. 281 - 290.
@article{d24a4b66f1c14e63905950eddf08cf05,
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 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.",
author = "Wootten, {Denise L} and Savage, {Emilia Elizabeth} and Celine Valant and May, {Lauren T} and Sloop, {Kyle W} and James Ficorilli and Showalter, {Aaron D} and Willard, {Francis S} and Arthur Christopoulos and Sexton, {Patrick M}",
year = "2012",
doi = "10.1124/mol.112.079319",
language = "English",
volume = "82",
pages = "281 -- 290",
journal = "Molecular Pharmacology",
issn = "1521-0111",
publisher = "ACS Books",
number = "2",

}

Allosteric modulation of endogenous metabolites as an avenue for drug discovery. / Wootten, Denise L; Savage, Emilia Elizabeth; Valant, Celine; May, Lauren T; Sloop, Kyle W; Ficorilli, James; Showalter, Aaron D; Willard, Francis S; Christopoulos, Arthur; Sexton, Patrick M.

In: Molecular Pharmacology, Vol. 82, No. 2, 2012, p. 281 - 290.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Allosteric modulation of endogenous metabolites as an avenue for drug discovery

AU - Wootten, Denise L

AU - Savage, Emilia Elizabeth

AU - Valant, Celine

AU - May, Lauren T

AU - Sloop, Kyle W

AU - Ficorilli, James

AU - Showalter, Aaron D

AU - Willard, Francis S

AU - Christopoulos, Arthur

AU - Sexton, Patrick M

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

UR - http://molpharm.aspetjournals.org/content/82/2/281.full.pdf

U2 - 10.1124/mol.112.079319

DO - 10.1124/mol.112.079319

M3 - Article

VL - 82

SP - 281

EP - 290

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 1521-0111

IS - 2

ER -