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PhD Studentship - Enzymatic Methods for Assembly of Nucleic Acid Therapeutic Agents

The University of Manchester - Department of Chemistry

Qualification Type: PhD
Location: Manchester
Funding for: UK Students, EU Students
Funding amount: Not Specified
Hours: Full Time
Placed On: 18th November 2021
Closes: 21st January 2022
 

This is a BBSRC DTP CASE studentship in partnership with Exactmer. Funding covers UK tuition fee and stipend only. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional candidates, due to the competitive nature of this scheme.

Supervisors: Professor Jason Micklefield & Professor Perdita Barran

Project title: Enzymatic methods for assembly of nucleic acid therapeutic agents

Project description:

Modified nucleic acids have emerged as a powerful new class of therapeutic agents for the prevention and treatment of a range of diseases (e.g. Inclisiran, a revolutionary cholesterol lowering drug (www.bbc.co.uk/news/health-58393866). Over 150 clinical trials are also ongoing using the main types of nucleic acid drugs, antisense oligonucleotides (ASOs) or small interfering RNAs (siRNA), for cancer, cardiovascular, neurodegenerative and infectious diseases etc. ASOs are short single stranded nucleic acids (oligonucleotides) that hybridise with messenger RNA (mRNA), modulating gene expression by blocking progression of the ribosome or inducing cleavage of the mRNA through recruitment of a ribonuclease enzyme (RNaseH). siRNA are short double stranded RNA molecules that bind to specific proteins in the cell to form a complex (RISC) which can cleave complementary mRNA targets. Despite their massive potential the production of these ‘magic bullets’ is extremely challenging, as extensive modification is required to evade nuclease degradation and to improve affinity for the mRNA target. In addition, their cellular uptake can be problematic, which often requires conjugation with other molecules to aid delivery. Currently solid phase synthesis is used to assemble ASOs and siRNAs. However, this requires an excess of costly precursors (monomers), toxic reagents, deleterious solvents and is very difficult to scale up, making treatments expensive and preventing development of new drugs. In this project we will develop more sustainable and scalable enzymatic methods to deliver essential ASO and siRNA medicines under mild conditions, in water, utilising more benign enzymes and renewable precursors. In collaboration with Exactmer (exactmer.com) we aim to: (i) Use directed evolution to engineer new enzymes that can assemble nucleotide monomers to generate target oligonucleotides with different chemical modifications; (ii) Explore the use of Exactmer’s membrane technology (Nanostar) platform for rapid assembly of target ASO and siRNA products, using the optimized enzymes; (iii) Establish more effective analytical methods (HPLC and mass spectrometry) to monitor the assembly and purify oligonucleotide products. Training will be provided in biological chemistry, biochemistry, enzymology, structural biology (X-ray crystallography), directed evolution, molecular biology and state-of-the-art analytical science under the supervision of Profs Jason Micklefield and Perdita Barran. The project will also involve close interactions with scientists from Exactmer, led by Prof Andrew Livingston, and will include a placement period at Exactmer where the student can obtain additional training and skills in leading industrial laboratories. Students from Chemistry or Biological Sciences degree programs, who wish to do cutting edge research at the Chemistry-Biology interface are encouraged to apply.

www.micklefieldlab.chemistry.manchester.ac.uk

www.research.manchester.ac.uk/portal/perdita.barran.html

exactmer.com

Entry Requirements

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

How to Apply

www.manchester.ac.uk/bbsrcdtpstudentships

Interested applicants should make contact with the Primary Supervisor to discuss the project as soon as possible.

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