New chemistry for RNA targeting therapeutics

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Antisense oligonucleotides (ASOs) are emerging as powerful precision medicines for life-threatening diseases. ASOs are short synthetic analogues of DNA that bind to RNA in a sequence specific manner, regulating gene expression and altering the production of disease-associated proteins. By targeting RNA, we can start to treat life-limiting conditions that cannot be addressed by conventional small molecule drugs, including cancers and inherited genetic diseases.Whilst this approach is promising, the current generation of ASOs suffer from poor efficacy, bioavailability, and potential toxicity, preventing their wider spread adoption. Advances in diagnostic technologies mean more and more untreatable diseases are coming within reach of ASOs, and new ASO chemistry is urgently needed to overcome these limitations.This project will develop a new class of ASO analogues that are designed to bind their target RNA with higher affinity and selectivity than the existing technology, potentially reducing the required dose and likelihood of toxic side effects. It will involve the development of new synthetic routes to prepare the ASO analogues, biophysical studies to investigate how well the new compounds interact with target RNA, and evaluation of their biological activity in cell-based assays.This is an interdisciplinary project and the student will receive training in a range of organic and chemical biology techniques during your studentship. These will include synthetic organic chemistry, solid-phase oligonucleotide and peptide synthesis, biophysical and biochemical techniques, and biological assays in cell culture.