Abstract
G protein-coupled receptors (GPCRs) are the largest class of drug targets, largely owing to their druggability, diversity and physiological efficacy. Many drugs selectively target specific subtypes of GPCRs, but high specificity for individual GPCRs may not be desirable in complex multifactorial disease states in which multiple receptors may be involved. One approach is to target G protein subunits rather than the GPCRs directly. This approach has the potential to achieve broad efficacy by blocking pathways shared by multiple GPCRs. Additionally, because many GPCRs couple to multiple G protein signalling pathways, blocking specific G protein subunits can 'bias' GPCR signals by inhibiting only a subset of these signals. Molecules that target G protein α or βγ-subunits have been developed and show strong efficacy in multiple preclinical disease models and biased inhibition of G protein signalling. In this Review, we discuss the development and characterization of G protein α and βγ-subunit ligands and the preclinical evidence that this exciting new approach has potential for therapeutic efficacy in a number of indications, such as pain, thrombosis, asthma and heart failure.
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Acknowledgements
A.V.S. is funded by grants from the NIH (NIHR01GM81772 and R35GM127303).
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Glossary
- Periaqueductal grey
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An anatomical region in the brainstem that surrounds the cerebral aqueduct. This region is enriched in opioid receptors that are thought to mediate the central analgesic actions of opioid analgesics.
- Hyperalgesia
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Increased sensitivity to pain. Repeated opioid treatment for chronic pain can paradoxically increase sensitivity to pain stimuli over time.
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Campbell, A., Smrcka, A. Targeting G protein-coupled receptor signalling by blocking G proteins. Nat Rev Drug Discov 17, 789–803 (2018). https://doi.org/10.1038/nrd.2018.135
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DOI: https://doi.org/10.1038/nrd.2018.135
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