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Supervisor 1:
Professor Barrie Kellam
Supervisor 2:
Professor Steve Hill
Funding Status: we will select the right option (competition funded studentships; Home and EU
student eligibility)
Application deadline: 16th January 2015
G-Protein Coupled Receptor Templated Chemistry; From Fluorescence Labelling to Ligand
Evolution
The Universities of Nottingham and Monash have launched a joint PhD programme at the cutting
edge of medicinal chemistry, molecular pharmacology and drug discovery and are recruiting
exceptional calibre applicants of any EU nationality for a 4-year research programme including a
full year of study at Monash University, Australia. Upon admission to the programme students
would undertake 3 rotations from a bank of available projects prior to selecting a final project.
G-protein coupled receptors (GPCRs) are prominent pharmacological targets but the design of
selective ligands remains a major therapeutic goal. To this end, we have established an international
reputation in both GPCR medicinal chemistry and molecular pharmacology which has significantly
contributed to this continuing area of fundamental research. In particular, we have established
ourselves as one of the leading groups associated with both the design and use of fluorescent
ligands to be able to interrogate GPCR function at both the cellular and sub-cellular level.1 This
project will build upon this track-record of research to explore two new aspects of GPCR medicinal
chemistry and pharmacology.
(i) The design of highly selective ligands, which are capable of covalently transferring a fluorescent
cargo to a region of a GPCR distal to the ligand-binding site. This has been previously
demonstrated to be possible for cellular proteins.2 Therefore, the ability to generate fluorescently
labelled wild-type GPCRs in their native cellular environment using this methodology will
significantly expand the spectral repertoire of fluorescent sensors applicable to GPCR imaging and
open up the possibilities of performing these chemical transformations in both primary and
recombinant cellular systems. Using this approach we will be able to combine this with our
previously established image-based methodologies3 to significantly enhance the means by which we
can interrogate monomeric and multimeric GPCR systems in their native cellular environment and
how they respond to ligand recognition. Using the adenosine receptor family as our initial model
template we will use our previous successes of generating highly selective fluorescent ligands for
this family6,7 to generate a range of ligand-fluorophore conjugates equipped with a range of reactive
linker moieties. We already have in-house homology models of the four receptor subtypes and
these will be employed to guide both the nature and placement of these reactive groups into the
conjugates to maximise exposure to suitable nucleophilic side-chain residues within the extracellular
loop regions.
(ii) Receptor Active-Site Controlled Ligand Evolution. As a further extension of utilising the
relationship between the receptor and its ligand, we also hypothesise that enhanced sub-type
selective GPCR agonists and antagonists can be developed using azide/acetylene-[1,3]-dipolar
cycloaddition in situ click chemistry4 in living cells via Receptor Active Site Controlled Ligand
Evolution (RASCLE). This concept has recently been validated using comparatively simpler systems
where purified soluble enzymes were used as templates to facilitate the synthesis of new
inhibitors.4,5 We will therefore investigate the ability to generate selective agonists at a membraneassociated protein, viz. the human adenosine A1 GPCR using In situ receptor-templated click
chemistry. This will be explored using a range of functionalised molecules which interact with either
the orthosteric or an allosteric site within the adenosine A1-receptor.
Interviews will take place in Nottingham in person or via Skype as appropriate.
Funding Notes: Students of UK and other EU nationalities are eligible to apply. Study fees and a
tax-free stipend of at least £13,863 (subject to confirmation) for 4-years (3 years in Nottingham plus
1 year at Monash) is provided. Travel expenses associated with the year of study in Australia will be
paid.
References:
1. Vernall et al. J. Med. Chem. 2012, 55, 1771–1782. 2. Hayashi et al. Acc Chem Res 2012, 45, 1460–
1469. 3. Corriden et al. FASEB J. 2014, 28, 4211–4222. 4. Mocharla et al. Angew. Chem., Int. Ed.
2005, 44, 116-120. 5. Krasiński, A. et al. J. Am. Chem. Soc. 2005, 127, 6686-6692. 6. Middleton et al.
J. Med. Chem. 2007, 50, 782–793. 7. Vernall et al Org. Biomol. Chem. 2013, 11, 5673–5682. 8.
Kourounakis, AP. et al. Drug Dev. Res. 2000, 49, 227-237.
Project classification: Synthetic Medicinal Chemistry
Application Enquiries:
Name: Professor Barrie Kellam
Email: barrie.kellam@nottingham.ac.uk
Applications: Applications consisting of a CV and covering letter should be sent to Professor Steve
Hill (stephen.hill@nottingham.ac.uk) or Dr Ian Kerr (ian.kerr@nottingham.ac.uk).