Therapeutic oligonucleotides are short DNA analogues which selectively bind to target mRNA through Watson-Crick base pairing to regulate the production of disease related proteins. Following the award of the 2006 Nobel Prize for RNA interfering technology and recent FDA approvals of several RNA-based therapeutics for the treatment of rare diseases, there has been significant investment into therapeutic oligonucleotides as a new drug modality. The increase in the number of potential therapeutics, including those for common diseases, creates a significant manufacturing challenge as existing methods of chemical synthesis are not suitable for large scale applications.
Within this project, we will investigate scalable biocatalytic approaches for therapeutic oligonucleotide manufacturing using the billion dollar drug Spinraza as a synthetic target. This project will involve evaluation of biocatalytic approaches based on the polymerase chain reaction, development of suitable biochemical assays (spectroscopic and LC-MS based methods), and directed evolution. X-ray crystallography of improved variants along the evolutionary trajectory will reveal the origins of increased catalytic efficiency, providing valuable insights to guide future generations of biocatalysts. This is a highly interdisciplinary project at the cutting edge of enzyme engineering research and will offer diverse training opportunities for a post-graduate student in a state-of-the-art multidisciplinary setting. The student will gain broad expertise in molecular and structural biology, protein expression and purification, directed evolution, biochemical assays and process development.
Academic background of candidates: Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in chemistry, biochemistry, biotechnology or related subject. A Masters degree and practical experience in a relevant subject area is desirable.