Background

Oligonucleotide (ON) therapeutics is an exciting clinically approved platform for the treatment of a range of diseases not readily accessible by small molecule drugs. In contrast to small molecules which mainly target proteins, therapeutic ONs bind to a target RNA sequence which results in the alteration of its function. Unmodified ONs which contain naturally occurring nucleotides are unsuitable for therapeutic applications and modifications to the ON scaffold are essential to improve their pharmacokinetic/pharmacodynamic properties such as cell uptake, metabolic stability, binding kinetics and selectivity for a target RNA sequence.

Project objective

The overall objective of this PhD studentship is to develop a new generation of sugar modifications on nucleoside scaffolds and their incorporation into therapeutic ONs.  Underpinning this medicinal chemistry project will be the development of new synthetic methodology to install fluorinated groups at defined positions within a sugar scaffold.  This project will involve extensive solution-phase and solid-phase synthesis, the development of novel synthetic methodology for stereoselective fluorination, biophysical evaluation and finally the exploration of their biological activity in cell lines.

Academic Environment

The student undertaking this project will receive unparalleled training in medicinal chemistry and nucleic acid chemical biology. The Burley group has extensive experience in small molecule and nucleoside synthesis, solid phase peptide/nucleic acid synthesis, biophysical analysis and structural biology.  The group has state-of-the-art automated synthesizers, HPLC equipment for purification and analysis, and mass spectrometry facilities. The Rattray group has extensive expertise and state-of-the-art facilities in the bioanalysis of oligonucleotides and bioconjugates.