New chemistry for RNA targeting therapeutics

反义寡核苷酸（ASO）正在成为治疗危及生命的疾病的强大精确药物。ASO是DNA的短合成类似物，其以序列特异性方式结合RNA，调节基因表达并改变疾病相关蛋白的产生。通过靶向RNA，我们可以开始治疗传统小分子药物无法解决的生命限制性疾病，包括癌症和遗传性遗传疾病。虽然这种方法很有前途，但目前这一代ASO的疗效、生物利用度和潜在毒性较差，阻碍了它们的广泛应用。诊断技术的进步意味着越来越多的无法治愈的疾病进入了ASO的治疗范围，迫切需要新的阿索化学来克服这些限制。本项目将开发一类新的阿索类似物，其设计目的是以比现有技术更高的亲和力和选择性结合其靶RNA，潜在地降低所需剂量和毒副作用的可能性。该项目将涉及开发新的合成路线以制备阿索类似物，生物物理研究以研究新化合物与靶RNA的相互作用，以及在基于细胞的测定中评估其生物活性。这是一个跨学科项目，学生将在学生期间接受一系列有机和化学生物学技术的培训。这些将包括合成有机化学，固相寡核苷酸和肽合成，生物物理和生物化学技术，以及细胞培养中的生物测定。

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.