Synthesis of Targeted Antiviral Nucleosides

靶向抗病毒核苷的合成

• 批准号: EP/V015087/1
• 负责人: Stephen Fletcher
• 金额: $ 46.11万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV015087%2F1
• 关键词: Synthesis; Targeted; Antiviral; Nucleosides

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.

该项目旨在解决针对 SARS-Cov-2 的抗病毒药物未得到满足的需求。我们将构建一组新的碳环 C 核苷，并测试它们作为导致 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，该疾病已导致全球超过 3,000,000 例感染和超过 200,000 例死亡（截至 2020 年 4 月 28 日）。我们拥有新技术，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良好的生物活性，但由于其合成困难，该基序作为抗病毒疗法尚未得到充分探索。所提出的方法能够有效合成多种结构，从而产生一个适合结构-活性关系研究和发现有效抗病毒疗法的化合物库。我们提出的目标与临床试验中的目标有很多相似之处，主要区别在于糖环中的氧原子被碳原子取代。我们方法的一个重要特点是能够生产多种相关化合物。文库合成后，将进行由 Ervin Fodor 进行的针对 SARS-Cov-2 病毒抑制测定的生物测试，并得到 Chris 的额外支持斯科菲尔德的分析开发和病毒酶学。有前景的化合物将与乔纳森·格莱姆斯 (Jonathan Grimes) 合作进行结构研究。所有项目合作伙伴均来自牛津大学。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治疗作用模式的理解，并能够设计出具有更大活性的小分子。

项目成果

Catalytic asymmetric synthesis of carbocyclic C-nucleosides

碳环C-核苷的催化不对称合成

• DOI: http://dx.10.1038/s42004-022-00773-6
• 发表时间: 2022
• 期刊: Communications Chemistry
• 影响因子: 5.9
• 作者: Mishra, Sourabh;Modicom, Florian C T;Dean, Conor L;Fletcher, Stephen P
• 通讯作者: Fletcher, Stephen P