Synthesis of Targeted Antiviral Nucleosides

该项目解决了针对SARS-Cov-2的抗病毒药物的未满足需求。我们将构建一组新的碳环C-核苷，并测试它们作为引起COVID-19的病毒的抑制剂。迫切需要抗病毒疗法来应对这种快速传播的病毒性疾病，截至2020年4月28日，这种疾病已导致全球超过3，000，000例感染和超过200，000例死亡。我们有新的技术可以快速构建碳环核苷库。尽管它们作为非天然核苷模拟物具有很好的生物活性，但由于其难以合成，该基序作为抗病毒疗法的探索不足。所提出的方法能够有效地合成各种各样的结构，从而产生用于结构-活性关系研究和发现有效的抗病毒疗法的化合物库。我们提出的靶点与临床试验中的靶点有很多相似之处，关键区别在于糖环中的氧原子被碳原子取代。我们的方法的一个重要特点是能够产生广泛的相关化合物。库的合成将随后进行生物学测试，由Ervin Fodor进行的针对SARS-Cov-2病毒的抑制试验，Chris斯科菲尔德在试验开发和病毒酶学方面提供额外的支持。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。探索小分子和RNA病毒复制机制之间相互作用的本质将增加我们对核苷治疗剂作用模式的理解，并有助于设计具有更大活性的小分子。

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.