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The design, synthesis and development synthetic transcriptional activators for the treatment of triplet expansion diseases

  • Full or part time
  • Application Deadline
    Thursday, January 31, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Background – A significant challenge of genetic medicine is to develop molecular therapies which can correct aberrant gene expression. This is a particularly challenging endeavour with genetic diseases such as Friedrich’s Ataxia (FRDA). FRDA arises when repeating sequences of DNA (GAA●TTC) build up in the frataxin gene (FXN). These DNA repeats act as a roadblock for the RNA polymerase II (RNAPII) enzyme to produce the full-length RNA sequence, which in turn results in a significant reduction in the production of the frataxin protein.

Project objective - The overall objective of this chemical biology studentship is to develop ‘synthetic transcription factors’ (syn-TFs) which enhance frataxin protein levels in FRDA cell lines by stimulating FXN transcription. In addition to developing synthetic methodology to prepare syn-TFs with enhanced drug-like properties, the student will have the opportunity to develop new deep sequencing methods, which report on the cell permeability and selectivity of FXN transcriptional activation.

Academic Environment - The student undertaking this project will receive unparalleled training in medicinal chemistry and in nucleic acid chemical biology. The Burley group has extensive experience in small molecule synthesis, solid phase peptide/nucleic acid synthesis, deep sequencing and bioconjugation.

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

Funding Notes

This studentship is open to Home/EU students and 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 Professor Glenn Burley () before the 31st January, 2019 deadline.

References

1. Hatit, M.Z.C.; Reichenbach, L.F.; Tobin, JM.; Vilela, F.; Burley, G.A.; Watson, A.J.B. “A flow platform for degradation-free CuAAC bioconjugation” Nature Communications (2018) 9, 4021.

2. Hayatigolkhatmi, K.; Padroni, G.; Su, W.; Fang, L.; Gómez-Castañeda, E.; Hsieh, Y-C.; Jackson L.; Holyoake, T.L.; Pellicano, F.; Burley, G.A.; Jørgensen, H.G. “Investigation of a minor groove-binding polyamide targeted to E2F1 transcription factor in chronic myeloid leukaemia (CML) cells” Blood, Cells, Molecules and Disease (2018) 69, 119-122.

3. Padroni, G.; Parkinson, J.A.; Fox, K.R.; Burley, G.A. "Structural basis of DNA duplex distortion induced by a thiazole-containing polyamide" Nucleic Acids Research (2018) 46, 42-43.

4. Jobbins, A.M.; Reichenbach, L.F.; Lucas, C.M.; Hudson, A.J.; Burley, G.A.; Eperon, I.C. "The mechanisms of mammalian splicing enhancers" Nucleic Acids Research (2018) 46, 2145-2158.

5. Fallows, A.J., Singh, I., Dondi, R., Cullis, P.M. Burley, G.A. "Highly efficient synthesis of DNA-binding polyamides using a convergent fragment-based approach" Organic Letters (2014) 16, 4654-4657.

How good is research at University of Strathclyde in Chemistry?
(joint submission with University of Glasgow)

FTE Category A staff submitted: 35.40

Research output data provided by the Research Excellence Framework (REF)

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