Endogenous allosteric modulators of G protein-coupled receptors

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Abstract

G protein-coupled receptors (GPCRs) are the largest superfamily of receptors encoded by the human genome, and represent the largest class of current drug targets. Over the last decade and a half, it has become widely accepted that most, if not all, GPCRs possess spatially distinct allosteric sites that can be targeted by exogenous substances to modulate the receptors biologic state. Although many of these allosteric sites are likely to serve other (e.g., structural) roles, they nonetheless possess appropriate properties to be serendipitously targeted by synthetic molecules. However, there are also examples of endogenous substances that can act as allosteric modulators of GPCRs. These include not only the obvious example, i.e., the G protein, but also a variety of ions, lipids, amino acids, peptides, and accessory proteins that display different degrees of receptor-specific modulatory effects. This also suggests that some GPCRs may possess true orphan allosteric sites for hitherto unappreciated endogenous modulators. Of note, the increasing identification of allosteric modulator lipids, inflammatory peptides, and GPCR-targeted autoantibodies indicates that disease context plays an important role in the generation of putative endogenous GPCR modulators. If an endogenous allosteric substance can be shown to play a role in disease, this could also serve as an impetus to pursue synthetic neutral allosteric ligands as novel therapeutic agents.
Original languageEnglish
Pages (from-to)246 - 260
Number of pages15
JournalJournal of Pharmacology and Experimental Therapeutics
Volume353
Issue number2
DOIs
Publication statusPublished - 2015

Cite this

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title = "Endogenous allosteric modulators of G protein-coupled receptors",
abstract = "G protein-coupled receptors (GPCRs) are the largest superfamily of receptors encoded by the human genome, and represent the largest class of current drug targets. Over the last decade and a half, it has become widely accepted that most, if not all, GPCRs possess spatially distinct allosteric sites that can be targeted by exogenous substances to modulate the receptors biologic state. Although many of these allosteric sites are likely to serve other (e.g., structural) roles, they nonetheless possess appropriate properties to be serendipitously targeted by synthetic molecules. However, there are also examples of endogenous substances that can act as allosteric modulators of GPCRs. These include not only the obvious example, i.e., the G protein, but also a variety of ions, lipids, amino acids, peptides, and accessory proteins that display different degrees of receptor-specific modulatory effects. This also suggests that some GPCRs may possess true orphan allosteric sites for hitherto unappreciated endogenous modulators. Of note, the increasing identification of allosteric modulator lipids, inflammatory peptides, and GPCR-targeted autoantibodies indicates that disease context plays an important role in the generation of putative endogenous GPCR modulators. If an endogenous allosteric substance can be shown to play a role in disease, this could also serve as an impetus to pursue synthetic neutral allosteric ligands as novel therapeutic agents.",
author = "{Van Der Westhuizen}, {Emma Therese} and Celine Valant and Patrick Sexton and Arthur Christopoulos",
year = "2015",
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language = "English",
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pages = "246 -- 260",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology & Experimental Therapeutics (ASPET)",
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T1 - Endogenous allosteric modulators of G protein-coupled receptors

AU - Van Der Westhuizen, Emma Therese

AU - Valant, Celine

AU - Sexton, Patrick

AU - Christopoulos, Arthur

PY - 2015

Y1 - 2015

N2 - G protein-coupled receptors (GPCRs) are the largest superfamily of receptors encoded by the human genome, and represent the largest class of current drug targets. Over the last decade and a half, it has become widely accepted that most, if not all, GPCRs possess spatially distinct allosteric sites that can be targeted by exogenous substances to modulate the receptors biologic state. Although many of these allosteric sites are likely to serve other (e.g., structural) roles, they nonetheless possess appropriate properties to be serendipitously targeted by synthetic molecules. However, there are also examples of endogenous substances that can act as allosteric modulators of GPCRs. These include not only the obvious example, i.e., the G protein, but also a variety of ions, lipids, amino acids, peptides, and accessory proteins that display different degrees of receptor-specific modulatory effects. This also suggests that some GPCRs may possess true orphan allosteric sites for hitherto unappreciated endogenous modulators. Of note, the increasing identification of allosteric modulator lipids, inflammatory peptides, and GPCR-targeted autoantibodies indicates that disease context plays an important role in the generation of putative endogenous GPCR modulators. If an endogenous allosteric substance can be shown to play a role in disease, this could also serve as an impetus to pursue synthetic neutral allosteric ligands as novel therapeutic agents.

AB - G protein-coupled receptors (GPCRs) are the largest superfamily of receptors encoded by the human genome, and represent the largest class of current drug targets. Over the last decade and a half, it has become widely accepted that most, if not all, GPCRs possess spatially distinct allosteric sites that can be targeted by exogenous substances to modulate the receptors biologic state. Although many of these allosteric sites are likely to serve other (e.g., structural) roles, they nonetheless possess appropriate properties to be serendipitously targeted by synthetic molecules. However, there are also examples of endogenous substances that can act as allosteric modulators of GPCRs. These include not only the obvious example, i.e., the G protein, but also a variety of ions, lipids, amino acids, peptides, and accessory proteins that display different degrees of receptor-specific modulatory effects. This also suggests that some GPCRs may possess true orphan allosteric sites for hitherto unappreciated endogenous modulators. Of note, the increasing identification of allosteric modulator lipids, inflammatory peptides, and GPCR-targeted autoantibodies indicates that disease context plays an important role in the generation of putative endogenous GPCR modulators. If an endogenous allosteric substance can be shown to play a role in disease, this could also serve as an impetus to pursue synthetic neutral allosteric ligands as novel therapeutic agents.

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