About the Project
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, affinity and selectivity for a target RNA sequence. Thus, an enduring challenge in the development of ON therapeutics is access to new modifications which enhance their drug-like properties without impacting efficacy.
Project objective
The overall objective of this PhD studentship is to develop new stereoselective methods for the preparation of fluorinated nucleoside building blocks. Underpinning this medicinal chemistry project will be the development of new methodology to install fluorinated groups at defined positions within the ribose sugar of nucleosides. This project will involve extensive solution-phase and solid-phase synthesis, the development of novel synthetic methodology for stereoselective fluorination, and finally establishing how these modifications influence engagement with a target RNA sequence, and their efficacy as a new modification for development in therapeutic ONs in cells.
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, deep sequencing and bioconjugation.
This is a 4 year EPSRC Industrial CASE studentship in collaboration with GlaxoSmithKline (GSK). The successful applicant will be expected to spend at least 3 months working alongside chemical biology groups at GSK’s Stevenage site.
References
Selected Publications
1. Padroni, G.; Withers, J.M.; Taladriz-Sender, A.; Reichenbach, L.F.; Parkinson, J.A.; Burley, G.A. “Sequence-selective minor groove recognition of a DNA duplex containing synthetic genetic components” Journal of the American Chemical Society, 2019, 141, 9555.
2. Hatit, M.Z.C.; Reichenbach, L.F.; Tobin, JM.; Vilela, F.; Burley, G.A.; Watson, A.J.B. “A flow platform for degradation-free CuAAC bioconjugation” Nature Communications 2018, 9, 4021.
3. Jobbins, A.M.; Reichenbach, L.F.; Lucas, C.M.; Hudson, A.J.; Burley. G.A.; Eperon. I.C. “The mechanisms of a mammalian splicing enhancer” Nucleic Acid Research, 2018, 46, 2145.
4. Weldon, C.; Behm-Ansmant, I.; Hurley, L.H.; Burley, G.A.; Branlant, C.; Eperon, I.C.; Dominguez, C. "Identification of G-quadruplexes in functional RNAs using FOLDeR" Nature Chemical Biology, 2016, 13, 18.
5. Smith, L.D., Dickinson, R.L, Lucas,C.M., Cousins, A., Malygin, A.A., Weldon, C., Perrett, A.J., Bottrill, A.R., Searle, M.S., Burley, G.A., Eperon, I.C. "A targeted oligonucleotide enhancer of SMN2 exon 7 splicing forms competing quadruplex and protein complexes in functional conditions" Cell Reports, 2014, 9, 193.
