PHARMACOGENOMICS Know Your GPCR Mutations (And Target Them Right)

RESEARCH HIGHLIGHTS

Nature Reviews Drug Discovery | Published online 1 Feb 2018; doi:10.1038/nrd.2018.13 mangsaab/iStock/Getty Images Plus

PHARMACOGENOMICS Know your GPCR mutations (and target them right)

Natural human genetic variations may within known functional sites, such MOR. Given the huge number of cause patients to respond differently as ligand binding, effector binding or drugs targeting the MOR that are to the same medication. Therefore, post-translational modification sites. prescribed, if even a small fraction understanding genetic variation in To explore the functional are ineffective or cause adverse drug targets can maximize efficacy implications of such mutations, the reactions, the economic burden and reduce side effects. In a new study, authors then experimentally analysed may be considerable. a team led by M. Madan Babu the impact of three MVs near the However, “as it stands, no receptor present a comprehensive analysis of ligand-binding pocket of the μ-opioid variants are included in the labelling G protein-coupled receptor (GPCR) receptor (MOR) on G protein activa- information of any GPCR drug genetic variants and find that GPCRs tion by the endogenous agonist endo- target by any regulatory agency,” says targeted by marketed drugs show morphine 1, morphine (full agonist), Alexander Hauser, first author of this genetic variation within functional buprenorphine (partial agonist) and study. “This is likely going to change regions such as drug-binding sites. naloxone (antagonist). Whereas one with increased sequencing efforts, GPCRs mediate the therapeutic variant (M153V) resulted in partial bigger cohorts and better character- effects of more than 30% of FDA- LoF and reduced the response to both ization of the variants”. Along with approved drugs. To assess how much full agonists and the partial agonist, the study, the authors also present an Looking variability is found among human another variant (K235N3) showed online resource of GPCR genetic across 108 GPCRs that are targeted by marketed increased efficacy and potency of variants (gpcrdb.org), which they GPCRs, the drugs, the authors investigated buprenorphine compared with the plan to update with new genome authors found data from the exome aggregation wild-type receptor. Another variant, data sets as well as orthogonal data consortium (ExAC), which contains V302I, showed gain-of-function types. “There is still a lot to under- over 14,000 information on missense variations effects with increased potencies of stand before we can fully embark on variants, with (MVs), loss-of-function variations full agonists and increased efficacy personalized medicine for GPCR- any individual (LoFs), and deletions and dupli- of the partial agonist. This variant targeted drugs. However, we think cations (copy number variations; maintained G protein signalling when the time is right to make a start”, receptor CNVs) from 60,000 individuals. treated with the antagonist naloxone. concludes M. Madan Babu. having an Looking across 108 GPCRs, the This finding indicates that naloxone, M. Teresa Villanueva average of authors found more than 14,000 which is used to treat opioid over- variants, with any individual receptor dose, may exhibit poor efficacy in ORIGINAL ARTICLE Hauser, A. S. et al. 4 common Pharmacogenomics of GPCR drug targets. Cell having an average of 4 common and patients with this variant receptor. 172, 41–54 (2017) and 128 rare 128 rare variations. They analysed The authors also considered the FURTHER READING Hauser, A. S. et al. Trends in variations each of the MVs and found that 2,036 possible economic impact of the GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 16, 829–842 (2017) mutations in the 108 receptors fall observed genetic variability in the