Novel Strategies Targeting G‐Protein‐Coupled Receptors: An Overview


G‐protein‐coupled receptors (GPCRs) represent the largest group of cell surface receptors encoded by the human genome (∼2%) and have been associated to a multitude of human disorders, which makes them the focus of attention of many drug discovery programs. Traditionally, the development of drugs that target GPCRs has been focused on finding agonists or antagonists that displace the natural or endogenous ligand to activate or inhibit the receptor. Emerging knowledge of structure and physiological functions of GPCRs has begun to alter the approaches to drug discovery. Thus, over the past two decades, novel strategies such as the development of biased and bitopic ligands, allosteric modulators, pepducins or ligands targeting GPCR heteromers have appeared. Some of these new approaches have proved to be productive, yielding molecules currently in clinical trials or even marketed.

Key Concepts

  • GPCRs are cell membrane proteins essential for the survival of eukaryotic cells and they can be classified in four different classes based on their amino acid sequence.
  • GPCRs are responsible for the realisation of cell functions through the transduction of a wide range of extracellular stimuli such as light, hormones, odours, peptides and neurotransmitters among others.
  • GPCRs are associated with a multitude of human disorders, in fact, medicines targeting these receptors comprise 35% of the drugs on the market.
  • Traditional approaches targeting GPCRs, that is development of agonists or antagonists that compete with the orthosteric or endogenous ligand, have become ineffective developing new drugs.
  • Selectivity across subtypes in a certain receptor family has been the major issue in order to obtain safer drugs.
  • The emergence of new and more sensitive pharmacological, biochemical and biophysical techniques have helped in designing novel strategies targeting GPCRs. The publication of crystal structures of GPCRs bound to various kind of ligands have been particularly helpful in determining the molecular basis of ligand binding.

Keywords: GPCR; biased ligand; bitopic ligand; allosteric modulator; pepducin; heteromer; drug discovery; medicinal chemistry

Figure 1. In the classical view of GPCR signalling, an agonist binds to the receptor, leading to its interaction with heterotrimeric G proteins (right). Activated α‐subunits subsequently bind to intracellular proteins such as adenylyl cyclase, RhoGEF and PLCβ and regulate their activity. These modulate downstream pathways directly or by generating second messengers (cAMP, DAG and IP3) that regulate further downstream effectors, such as protein kinase A and C (PKA and PKC). Following their liberation from the heterotrimeric G protein complex, the βγ‐subunits can also bind to and regulate certain downstream effectors, such as ion channels and PLCβ. Alternative signalling pathways may be triggered if arrestin binds to the intracellular side of the GPCR (left), instead of the G protein. These include interaction with effector proteins such as MAPKs, tyrosine kinases or E3 ubiquitin ligases.
Figure 2. Structures of the two marketed GPCR AMs.
Figure 3. Ligands targeting GPCR heterodimer complexes produce an effect different from that upon binding to each individual receptor on its own, displaying novel pharmacological properties.


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García‐Cárceles, Javier(Nov 2018) Novel Strategies Targeting G‐Protein‐Coupled Receptors: An Overview. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028406]