New and Versatile Approach to Synthesis of chemRNA

Lead Research Organisation: University of Oxford
Department Name: Interdisciplinary Bioscience DTP

Abstract

mRNA expression often requires demanding procedures or specific enzymatic steps. We propose an alternative strategy utilising chemically ligated RNA (chemRNA) with the aim to enhance procedures such as in vitro transcription, improve RNA stability and allow for site specific modifications. chemRNA will be ligated, using amide linkages and triazole copper click reactions. This modular approach has a unique advantage allowing for protein production from both natural and modified sequences. Our intention is to optimise the synthesis of chemRNA, investigate the fidelity of chemRNA in biological mechanisms and synthesise proteins from enhanced chemRNA. We consider this work to fall within three priority areas of the BBRSC. chemRNA has good potential for scale-up applications in industrial biotechnology. It is a new synthetic approach that is key to advances in synthetic biology and can be used as a universal technique for the advancement of the biosciences.


AfS, ENWW

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011224/1 01/10/2015 30/09/2023
1801885 Studentship BB/M011224/1 01/10/2016 20/01/2021 Cameron Jean Thorpe
 
Description During the first half of the award research has focused on development of modified RNA oligonucleotides with modified carbamate, amide and triazole backbones. We have confirmed that they process good enzymatic properties which is important for therapeutic use. A drawback of some of these modifications, is that they can reduce duplex stability, a required property for target binding. Combing these backbones with locked nucleic acids (LNA), a sugar modification, resulted in restoration of duplex stability and further reduced enzymatic susceptibility. The significance of these findings suggests that use of these modifications could provide us with new building blocks for the design RNA therapeutic templates. Applications can be found to treat a wide range of hereditary and genetic deceases such as Muscular Dystrophy or Familial Hypercholesterolemia.
Exploitation Route Our development of modified chemRNA provides a building block that can be incorporated into oligonucleotide RNA templates using standard solid state synthesis. This well defined method is widely used within academia and industry allowing our finding to be easily adapted to different applications not only for therapeutic use. Incorporation into antisense drugs could improve efficacy or high stability could be utilized for long term biological data storage applications. Synthesis and development of these modifications are easily adapted to large scale production if required for pharmaceutical use.
Sectors Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology