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Synthesis of ribonucleosides using biocatalytic cascades


Project Description

Background – Current state of the art for the synthesis of Anti-Sense Oligonucleotides employs solid phase synthesis. The ASOs are assembled from individual ribonucleotides which themselves are often requiring complicated multistep routes to prepare.

Aims – In this project we propose to utilise biocatalysis as a basis for designing a de novo synthetic strategy for ribonucleotide synthesis. Synthesis of a ribonucleoside via a biocatalytic cascade would minimise the use of nucleoside protecting groups by exploiting the natural specificity of biocatalysts. This project will involve the use of multiple enzyme cascades for synthesis of the ribonucleoside.

Year 1 – Enzyme cascade identified, all enzyme sequences identified, enzymes expressed in E. coli with initial characterization.
Year 2 – Libraries of enzymes generated, screened and enhanced variants identified, synthesis of ribose moiety demonstrated.
Year 3 – Development of multi-step synthesis for ribonucleotide intermediates, explore potential chemo-enzymatic systems.
Year 4 – Demonstration of multi-enzymatic/chemoenzymatic cascade synthesis of ribonucleotides.

We welcome applications from graduates with a good UK honours undergraduate degree (1st class or a high 2i), or a first degree with an additional masters degree or international equivalent, in chemistry, biochemistry, biology or another aligned science subject. Applicants should be looking for a challenging, interdisciplinary research training environment.

All applicants should send their CV and covering letter to Dr Ian Rowles (CBNM Project Manager) . Applications will be reviewed as they are received until a candidate is selected; therefore candidates are encouraged to apply early.

Funding Notes

This is a 4 year studentship jointly funded by the EPSRC, AstraZenca and the University of Manchester, covering all fees and stipend (£14.777 in September 2018). Open to UK/EU applicants only.

The start date for this PhD prgramme will be September 2019.

References

1. P.P. Seth et al., J. Org. Chem., 2010, 75, 1569
2. M. Pickl et al., Appl. Microb. Biotech., 2015, 99, 6617
3. P. Clapes et al., Curr. Opin. Chem. Biol., 2010, 14, 154
4. D. Ubiali et al., Adv. Synth. Catal., 2012, 354, 96

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