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EPSRC-GSK iCASE Studentship: Mechanism-inspired development of a new chemical biology tagging platform to probe prostate cancer glycobiology

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  • Full or part time
    Dr Glenn Burley
    Dr Allan Watson
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Background – The post-genomic era has provided biologists with a wealth of information and –omic sequencing tools to further our understanding of fundamental biology and disease. However, it is still exceedingly difficult to interrogate biological processes where the link between gene and protein expression is decoupled. A pertinent exemplar of this is changes in the glycosylation state between healthy and cancerous cells presented on the cell surface. An emerging tool used to interrogate these changes is the metabolic incorporation of ‘chemical reporters’ within a target biomolecule and access to highly specific ‘bio-orthogonal’ chemical reactions, which preferably react only with the chemical reporter group. Key to the success of this approach is the availability of bio-orthogonal reactions that are fast, biocompatible, and chemoselective.

The incorporation of two chemical reporters followed by chemoselective bio-orthogonal labelling is an extension of this ‘tag and modify’ strategy, which offers the opportunity to label two different biomolecules in cellulo. Additionally, the incorporation of different chemical reporters within a single biomolecule followed by dual differential labelling is a nascent approach to probe the dynamics of a single biomolecule. At present, this is highly challenging to achieve with current bio-orthogonal strategies if discretely tagged products (i.e., without a mixture of products) are required.

Previous work – Our collaborative team has recently identified the utility of aromatic ynamines as a superior reagent for Cu-catalyzed alkyne-azide cycloaddition (CuAAC) reactions.[1-2] These alkyne surrogates require significantly less Cu catalyst are the only alkyne reagents reported to date which enable chemoselective control in a sequential two-step CuAAC process.[1,3]

Project Objective - The principal objective of this studentship is to develop aromatic ynamines into a powerful new bio-orthogonal reaction platform for the chemoselective tagging of glycoproteins in prostate cancer cells.

The specific aims of the project are to:

(i) understand the origin of enhanced chemoselectivity of ynamines in CuAAC reactions, and potentially across other bio-orthogonal reaction classes.

(ii) establish conditions for chemoselective modification of biomolecules.

(iii) explore the utility of ynamines as glycoprotein tagging agents of prostate cancer cells.

Academic Environment - The student undertaking this project will receive unparalleled experience in all aspects of mechanistic organic chemistry and cancer chemical biology within our inter-disciplinary collaboration. The Burley group (www.burleylabs.co.uk, University of Strathclyde) has extensive experience in small molecule synthesis, solid phase peptide/nucleic acid synthesis and the development of bioconjugation reagents. The Watson group (University of St. Andrews, http://www.watsonresearchgroup.co.uk) has specialised expertise in mechanistic organic chemistry and has applied this mechanistic insight to develop improved chemical processes for a suite of C-C, C-O and C-N bond forming methods. The cell uptake and selectivity experiments will be conducted in collaboration with Prof David Elliott and his team in Northern Institute for Cancer Research (Newcastle University).

Funding Notes

This is an EPSRC Industrial CASE studentship in collaboration with GlaxoSmithKline (GSK). The successful applicant will spend at least 3 months working alongside Chemical Biology groups at GSK’s Stevenage site.

This studentship is open to Home/EU students includes a stipend and fees for 4 years.

Candidates must have a strong background in Synthetic Organic or Medicinal/Biological Chemistry and have obtained a (i) or 2(i) [or equivalent for EU students] degree.

Candidates who are interested in this position are encouraged to send their CV and contact details of two referees to [Email Address Removed] before the 20th January, 2018 deadline.

References

1. Hatit, M.Z.C.; Sadler, J.C.; McLean, L.A.; Whitehurst, B.C.; Seath, C.P.; Humphreys, L.D.; Young, R.J.; Watson, A.J.B.; Burley, G.A. "Chemoselective Sequential Click Ligations Directed by Enhanced Reactivity of an Aromatic Ynamine" Organic Letters, 2016, 18, 1694-1697.

2. Seath, C.P.; Burley, G.A. & Watson, A.J.B. "Determining the Origin of Rate-Independent Chemoselectivity in CuAAC Reactions: An Alkyne-Specific Shift in Rate-Determining Step" Angewandte Chemie International Edition, 2017, 56, 334-3318.

3. Hatit, M.Z.C.; Seath, C.P.; Watson, J.B.; Burley, G.A. "A Strategy for Conditional Orthogonal Sequential CuAAC Reactions Using a Protected Aromatic Ynamine" Journal of Organic Chemistry, 2017, 82, 5461-5468.

4. Perrett, A.J.; Dickinson, R.L.; Krpetic, Z., Brust, M.; Lewis, H.; Eperon, I.C.; Burley, G.A. "Conjugation of PEG and gold nanoparticles to increase the accessibility and valency of tethered RNA splicing enhancers" Chemical Science, 2013, 4, 257-265.


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