Targeting receptor complexes: a new dimension in drug discovery

Abstract

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.

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Fig. 1: Structure and function of receptor complexes.
Fig. 2: Strategies for targeting receptor complexes.
Fig. 3: Targeting ligand-gated ion channel complexes.
Fig. 4: Targeting GPCR complexes.

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M.I.R. is a full-time employee of Novo Nordisk at the time of publication. K.S. is a co-founder and a part-time employee of Avilex Pharma. B.B. is a member of the scientific advisory board of Addex Therapeutics, Geneva. L.S.C. is a full-time employee of BioInnovation Institute. D.S.B. is a full-time employee of Janssen Pharmaceuticals.

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Glossary

Blood–brain barrier

The blood–brain barrier strictly restricts which molecules can enter the brain, and it comprises tight junctions between endothelial cells, astrocytic endfeet and a basement membrane.

Scaffolding protein

A protein that organizes multiple proteins into a functional protein complex.

Desensitization

A mechanism that uncouples downstream receptor signalling during prolonged activation to attenuate the excessive cellular effects.

Phenotypic drug discovery

A screening method to identify compounds with desired biological phenotypes that is agnostic of the molecular target.

DNA-encoded chemical libraries

(DELs). Large collections of small molecules (up to 109) whose structure is connected to a unique DNA sequence, allowing pooled screening. Sequencing of screening hits subsequently allows chemical identification.

Targeted protein degradation

A technology that targets a protein of interest for degradation by using the cellular degradation machinery, such as the ubiquitin–proteasome system.

Cell-penetrating peptides

Short peptide sequences that promote the cellular uptake of various cargoes, such as peptides, proteins and oligonucleotides.

Excitotoxicity

A process in which neurons are damaged owing to excessive activation of glutamate receptors.

Functional proteomics

A proteomic approach that aims to elucidate and identify interacting proteins of stable protein complexes.

Biased signalling

A concept of receptor modulation that allows selective pharmacological activation of one downstream signalling pathway over others.

Nootropic effects

A general term that describes improved cognitive functions.

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Rosenbaum, M.I., Clemmensen, L.S., Bredt, D.S. et al. Targeting receptor complexes: a new dimension in drug discovery. Nat Rev Drug Discov 19, 884–901 (2020). https://doi.org/10.1038/s41573-020-0086-4

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