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G-Protein Coupled Receptors as therapeutic targets in drug discovery

Project Description

G-protein coupled receptors (GPCRs) are the largest family of membrane proteins in humans and as a result are a common target for the pharmaceutical industry.[1] Currently, >25% of drugs on the market target GPCRs, demonstrating their importance in medicine. GPCRs are a superfamily of transmembrane proteins that interact with G-proteins and contain seven helices with interconnecting loops. Over 800 unique GPCRs have been located in the human genome and can be clustered into 5 families based on amino acid sequence similarities.[2] The function of a GPCR is to detect extracellular stimuli and to exert an intracellular response. GPCRs account for a variety of physiological functions, which make them ideal drug targets.
For many years GPCRs were believed to exist as monomers only. However, it is now accepted that GPCRs can form ‘receptor heterodimers’.[3] This is when receptors of different gene families combine among themselves to generate new and unique biochemical/functional characteristics that are distinct from the single receptor. These heterodimers constitute an important and emerging area in GPCR drug discovery[4] with recent studies validating modulation of heterodimers as an effective therapeutic intervention.[5-7]
In addition, there are a number of GPCRs whose natural endogenous ligands are unknown and these are referred to as orphan GPCRs. To date, there are approximately 140 known orphan GPCRs.[8] Orphan GPCRs are unexplored drug targets present in most of the bodies tissue, with many having been implicated in various diseases such as cancer and Alzheimer’s disease. Orphan GPCRs therefore have the potential to be very significant in drug discovery.[8]
Our group is interested in harnessing the therapeutic potential of GPCRs; specifically designing small molecules or peptides that can be used as chemical probes to further our understanding of the biology of the receptors or as lead compounds for drug discovery.

Funding

Applicants wishing to apply for PhD funding through external scholarship providers are welcomed (see website for details of QMUL's international funding partners), as are those applicants who can self-fund.

Eligibility and Applying

Applicants must have an undergraduate degree in chemistry or pharmacy awarded with upper second class honours. 

Details of the application process can be found on this webpage.

References

  1. A. S. Hauser, M. M. Attwood, M. Rask-Andersen, H. B. Schiöth, D. E. Gloriam, Trends in GPCR drug discovery: new agents, targets and indications, Nature Reviews Drug Discovery, 2017, 16, 829–842
  2. K. Sriram, P. A. Insel, GPCRs as targets for approved drugs: How many targets and how many drugs?, Molecular Pharmacology 2018, mol.117.111062; DOI:https://doi.org/10.1124/mol.117.111062
  3. S. Ferré, V. Casadó, L. A. Devi, M. Filizola, R. Jockers, M. J. Lohse, G. Milligan, J. P. Pin, X. Guitart, G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacological Reviews, 2014, 66, 413-434.
  4. R. Franco, E. Martínez-Pinilla, A. Ricobaraza, P.J. McCormick, Challenges in the development of heteromer-GPCR-based drugs, Progress in Molecular Biology and Translational Science, 2013, 117, 143-162.
  5. L. Pei, S. Li, M. Wang, M. Diwan, H. Anisman, P.J. Fletcher, J.N. Nobrega, F. Liu, Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects, Nature Medicine, 2010, 16, 1393-1395.
  6. X. Viñals, E. Moreno, L. Lanfumey, A. Cordomí, A. Pastor, R. de La Torre, P. Gasperini, G. Navarro, L. Howell, L. Pardo, L., C. Lluís, E. I. Canela, P. J. McCormick, R. Maldonado, P. Robledo, Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors, PLoS Biology, 2015, 13, [e1002194].
  7. M. L. Perreault, A. Hasbi, B. F. O'Dowd, S. R George, Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance, Neuropsychopharmacology. 2014, 39, 156-168.
  8. J. A. Stockert, L. A. Devi, Advancements in therapeutically targeting orphan GPCRs, Front. Pharmacol., 2015 | https://doi.org/10.3389/fphar.2015.00100
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