伪尿嘧啶和 N1-甲基伪尿嘧啶是用于 RNA 治疗和疫苗开发的强效核苷酸类似物

IF 4.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY RSC Chemical Biology Pub Date : 2024-03-19 DOI:10.1039/D4CB00022F
Lyana L. Y. Ho, Gabriel H. A. Schiess, Pâmella Miranda, Gerald Weber and Kira Astakhova
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摘要

经过修饰的核苷是现代药物开发不可或缺的组成部分,是创造更安全、更有效和更精确的靶向治疗干预措施的重要基石。核苷酸修饰作为单体通常具有抗病毒和抗癌活性。当加入核酸寡聚体中时,它们能提高稳定性,防止酶的降解,从而延长药物在体内的寿命。此外,修饰策略还能减轻潜在的毒性效应,降低免疫原性,使药物更安全,耐受性更好。其中,N1-甲基假尿嘧啶修饰提高了COVID-19尖峰蛋白的mRNA编码效率。这成为开发在 2020 年大流行期间应用的 COVID-19 疫苗的关键一步。这使得 N1-甲基伪尿嘧啶及其 "母体 "类似物伪尿嘧啶成为未来 RNA 治疗和疫苗开发的有效核苷酸类似物。本综述重点介绍假尿嘧啶和 N1-甲基假尿嘧啶的结构和特性。与 DNA 相比,RNA 具有更大的结构多样性、不同的构象和化学反应性。具有更多不常见碱基对和碱基三胞胎的 RNA 并不严格遵循沃森-克里克配对。这就需要对 RNA 进行详细的结构研究和结构-活性关系分析,同样也需要对 RNA 进行修饰。本综述回顾了最近在这方面取得的成功。我们介绍了最近在 mRNA 候选药物中使用假尿嘧啶和 N1-甲基假尿嘧啶所取得的成功。我们还强调了开发新的 mRNA 疫苗和疗法仍需解决的难题。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Pseudouridine and N1-methylpseudouridine as potent nucleotide analogues for RNA therapy and vaccine development

Modified nucleosides are integral to modern drug development, serving as crucial building blocks for creating safer, more potent, and more precisely targeted therapeutic interventions. Nucleobase modifications often confer antiviral and anti-cancer activity as monomers. When incorporated into nucleic acid oligomers, they increase stability against degradation by enzymes, enhancing the drugs’ lifespan within the body. Moreover, modification strategies can mitigate potential toxic effects and reduce immunogenicity, making drugs safer and better tolerated. Particularly, N1-methylpseudouridine modification improved the efficacy of the mRNA coding for spike protein of COVID-19. This became a crucial step for developing COVID-19 vaccine applied during the 2020 pandemic. This makes N1-methylpseudouridine, and its “parent” analogue pseudouridine, potent nucleotide analogues for future RNA therapy and vaccine development. This review focuses on the structure and properties of pseudouridine and N1-methylpseudouridine. RNA has a greater structural versatility, different conformation, and chemical reactivity than DNA. Watson–Crick pairing is not strictly followed by RNA that has more unusual base pairs and base-triplets. This requires detailed structural studies and structure–activity relationship analyses for RNA, also when modifications are incorporated. Recent successes in this direction are revised in this review. We describe recent successes with using pseudouridine and N1-methylpseudouridine in mRNA drug candidates. We also highlight remaining challenges that need to be solved to develop new mRNA vaccines and therapies.

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CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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