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  Chemical evolution of artificial oligonucleotide catalysts for ultra-specific RNA detection and knockdown


   Department of Chemistry

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  Dr Alex Taylor  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Beyond information storage, single-stranded nucleic acids can adopt complex 3D structures with biochemical activities, e.g. antisense oligonucleotides (ASOs), chemical antibodies (aptamers) and catalysts (ribozymes, DNAzymes). Such ‘functional oligos’ combine the advantageous properties of small molecules with the sophistication of complex biologics like monoclonal antibodies and enzymes, in principle offering a wealth of molecular tools and technologies for research, diagnosis and therapy - yet synthesised and stored as easily as a PCR primer. However, widespread clinical application of functional oligos have been hampered by the limitations of natural DNA or RNA backbones – human biology has several mechanisms for rapidly destroying or developing immune responses to foreign DNA & RNA.

Beyond nature’s chemistry, nucleic acid analogues with divergent structures and physicochemical properties, known as Xeno-nucleic acids (XNAs),  offer a route to novel functional molecules with improved biostability, efficacy, and reduced immunogenicity. Such modified nucleic acid chemistries have enabled the clinical translation of several ASO therapeutics, silencing RNAs (RNAi) and the recent COVID-19 mRNA vaccines. Using engineered polymerases, a variety of XNAs can be used as synthetic genetic polymers, enabling the discovery and evolution of fully-artificial XNA structures with biochemical function[1].

We have shown that in addition to proteins and RNA, enzymes can evolve from a variety of polymer chemistries beyond those found in biology (at least on Earth!)[2]. Such artificial XNA enzymes - “XNAzymes” – include RNA-cleaving catalysts that could provide form the basis of platform technologies for ultra-specific RNA knockdown or detection – an increasingly pressing challenge in biomedicine, as a huge variety of RNAs are key players in virtually every cellular process and disease, offering a vast array of underexploited drug targets. XNAzymes can be ‘reprogrammed’ to target disease-associated mRNAs[3], non-coding RNAs[4] and viral genomic RNAs[5], and perform RNA cutting with single-nucleotide precision – e.g. cleaving mRNAs only when oncogenic point mutations are present and leaving wild type (healthy) sequences alone. Compared with other RNA-modulating technologies, XNAzymes do not rely on co-delivery or expression of protein enzymes, or co-opting cells’ silencing machinery, in principle greatly reducing their capacity for off-target effects.

This project will explore incorporation of novel XNA chemistries and test-tube evolution methods into the XNAzyme discovery and engineering process to improve their catalytic power and elucidate their activity inside cells. The project will involve organic chemistry (molecular synthesis), chemical biology and a variety of molecular and cellular biology methods (directed evolution, RT-qPCR, deep sequencing, tissue culture). This is an exciting opportunity to be involved in cutting-edge research spanning fundamental synthetic biology and pre-clinical development of novel biotechnologies.

Student Profile

Applicants must have or be predicted to obtain a BSc or Master’s degree with first class (1) or upper second class (2:1) honours in Chemistry, Biochemistry, Molecular Biology or other related subject.

Candidates should be able to demonstrate an aptitude for research, the ability to work collaboratively in a diverse research environment as well as problem-solving and independence. This position will suit a candidate with an interest in synthetic biology and chemical biology.

Application Procedure

To be considered for the position candidates must apply via King’s Apply online application system. Details are available at Postgraduate taught and research courses | Department of Chemistry | King’s College London (kcl.ac.uk)

Please select “Chemistry Research MPhil/PhD” as the research programme.

Please indicate Dr Alex Taylor as the supervisor and quote research group Taylor in your application and all correspondence.

Applications, including a cover letter, a full up-to-date CV, together with the names, addresses and email addresses of two academic referees should also be sent as soon as possible to Dr Alex Taylor ([Email Address Removed]).

If you require support with the application process, please contact the Chemistry Postgraduate Research Officer Síle Maguire Conneely ([Email Address Removed])

The selection process will involve a pre-selection on documents and, if selected, will be followed by an invitation to an interview. If successful at the interview, an offer will be provided in due time.

Chemistry (6) Engineering (12)

Funding Notes

Funding is available for 4 years and covers tuition fees, consumables fees of c. £4500 per annum and a tax-free stipend of approximately £20,622 p.a. (as of the 23/24 academic year, subject to change) with possible inflationary increases after the first year.

References

[1] Taylor, A.I., Houlihan, G. and Holliger, P. (2019) Beyond DNA and RNA: the expanding toolbox of synthetic genetics, CSH Perspectives in Biology 11(6), a032490.
[2] Taylor, A.I. et al. (2015) Catalysts from synthetic genetic polymers, Nature 518, 427-430.
[3] Taylor, A.I. et al. (2022) A modular XNAzyme cleaves long, structured RNAs under physiological conditions and enables allele-specific gene silencing, Nature Chemistry 14, 1295-1305.
[4] Donde, M.J. Rochussen, A.M., Kapoor, S. and Taylor, A.I. (2022) Targeting non-coding RNA family members with artificial endonuclease XNAzymes, Communications Biology 5, 1010.
[5] Pereyra Gerber, P., Donde, M.J., Matheson, N.J. and Taylor, A.I. (2022) XNAzymes targeting the SARS-CoV-2 genome inhibit viral infection, Nature Communications 13, 6716.
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