TY - JOUR
T1 - Targeting receptor complexes
T2 - a new dimension in drug discovery
AU - Rosenbaum, Mette Ishoy
AU - Clemmensen, Louise S.
AU - Bredt, David S.
AU - Bettler, Bernhard
AU - Stromgaard, Kristian
PY - 2020
Y1 - 2020
N2 - Targeting receptor proteins, such as ligand-gated ion channels and G protein-coupled receptors, has directly enabled the discovery of most drugs developed to modulate receptor signalling. However, as the search for novel and improved drugs continues, an innovative approach - targeting receptor complexes - is emerging. Receptor complexes are composed of core receptor proteins and receptor-associated proteins, which have profound effects on the overall receptor structure, function and localization. Hence, targeting key protein-protein interactions within receptor complexes provides an opportunity to develop more selective drugs with fewer side effects. In this Review, we discuss our current understanding of ligand-gated ion channel and G protein-coupled receptor complexes and discuss strategies for their pharmacological modulation. Although such strategies are still in preclinical development for most receptor complexes, they exemplify how receptor complexes can be drugged, and lay the groundwork for this nascent area of research.Targeting protein complexes, including those containing G protein-coupled receptors or ligand-gated ion channels, could provide opportunities to increase the target and functional selectivity of novel drugs compared with existing therapies, which only target the receptors. This Review discusses the landscape of ligand-gated ion channel and G protein-coupled receptor complexes as therapeutic targets, as well as strategies for their pharmacological modulation.
AB - Targeting receptor proteins, such as ligand-gated ion channels and G protein-coupled receptors, has directly enabled the discovery of most drugs developed to modulate receptor signalling. However, as the search for novel and improved drugs continues, an innovative approach - targeting receptor complexes - is emerging. Receptor complexes are composed of core receptor proteins and receptor-associated proteins, which have profound effects on the overall receptor structure, function and localization. Hence, targeting key protein-protein interactions within receptor complexes provides an opportunity to develop more selective drugs with fewer side effects. In this Review, we discuss our current understanding of ligand-gated ion channel and G protein-coupled receptor complexes and discuss strategies for their pharmacological modulation. Although such strategies are still in preclinical development for most receptor complexes, they exemplify how receptor complexes can be drugged, and lay the groundwork for this nascent area of research.Targeting protein complexes, including those containing G protein-coupled receptors or ligand-gated ion channels, could provide opportunities to increase the target and functional selectivity of novel drugs compared with existing therapies, which only target the receptors. This Review discusses the landscape of ligand-gated ion channel and G protein-coupled receptor complexes as therapeutic targets, as well as strategies for their pharmacological modulation.
KW - GENE-RELATED PEPTIDE
KW - PROTEIN-PROTEIN INTERACTIONS
KW - SMALL-MOLECULE INHIBITORS
KW - NATIVE GABA(B) RECEPTORS
KW - NEURONAL NITRIC-OXIDE
KW - PICK1 PDZ DOMAIN
KW - AMPA RECEPTORS
KW - DOUBLE-BLIND
KW - AUXILIARY SUBUNITS
KW - SULFONYLUREA RECEPTOR
U2 - 10.1038/s41573-020-0086-4
DO - 10.1038/s41573-020-0086-4
M3 - Review
C2 - 33177699
VL - 19
SP - 884
EP - 901
JO - Nature Reviews. Drug Discovery
JF - Nature Reviews. Drug Discovery
SN - 1474-1776
ER -