Synthesis of Targeted Antiviral Nucleosides

该项目解决了针对SARS-CoV-2的抗病毒药物的未得到满足的需求。我们将构建一组新的碳环C-核苷，并测试它们作为导致新冠肺炎的病毒的抑制剂。迫切需要抗病毒疗法来应对这种迅速传播的病毒性疾病，这种疾病已导致全球300多万人感染和20多万人死亡(截至2020年4月28日)。我们有新技术，可以快速建立碳环核苷文库。尽管它们作为非天然核苷模拟物具有很好的生物活性，但由于其合成困难，作为抗病毒治疗的研究还不够深入。所提出的方法能够有效地合成一系列不同的结构，从而产生一个化合物文库，为结构-活性关系研究和发现有效的抗病毒疗法奠定基础。我们提出的目标与临床试验中的目标有很大的相似之处，关键的区别是用碳原子取代了糖环中的氧原子。我们方法的一个重要特点是能够产生广泛的相关化合物。文库合成后，将在Ervin Fodor进行的抗SARS-CoV-2病毒抑制试验中进行生物学测试，克里斯·斯科菲尔德还将在测试开发和病毒酶学方面提供支持。有希望的化合物将与乔纳森·格里姆斯合作进行结构研究。所有项目合作伙伴都在牛津大学。探索小分子与RNA病毒复制机制之间相互作用的本质将增加我们对核苷疗法作用模式的理解，并使小分子的设计具有更大的活性。

This project tackles the unmet need for antiviral drugs targeted against SARS-Cov-2. We will construct a set of new carbocyclic C-nucleosides and test them as inhibitors of the virus which causes COVID-19. Antiviral therapies are urgently required to tackle this rapidly transmitted viral disease, which has resulted in over 3,000,000 infections and over 200,000 deaths globally (as of 28th April 2020). We have new technology which will enable the rapid construction of a library of carbocyclic Cnucleosides. Despite their promising biological activity as non-natural nucleoside mimics, this motifis underexplored as an antiviral therapy on account of its difficult synthesis. The proposed approach enables the efficient synthesis of a diverse range of structures, resulting in a compound library primed for structure-activity relationship studies and the discovery of effective antiviral therapies. There is much similarity between the targets we propose and those in clinical trials, with the key difference being replacement of the oxygen atom in the sugar ring with a carbon atom. An important feature of our approach is the ability to produce a wide range of related compounds.The synthesis of the library will be followed by biological testing in inhibition assays against the SARS-Cov-2 virus conducted by Ervin Fodor, with additional support from Chris Schofield on assay development and viral enzymology. Promising compounds will be subjected to structural studies,in collaboration with Jonathan Grimes. All project partners are at the University of Oxford. Probing the nature of the interaction between the small molecules and the RNA virus replication machinery will increase our understanding of the mode of action of nucleoside therapeutics andenable the design of small molecules with even greater activity.