Advances in structural-guided modifications of siRNA

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic & Medicinal Chemistry Pub Date : 2024-06-28 DOI:10.1016/j.bmc.2024.117825

Qiang Li , Mingxin Dong , Pu Chen

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Abstract

To date, the US Food and Drug Administration (FDA) has approved six small interfering RNA (siRNA) drugs: patisiran, givosiran, lumasiran, inclisiran, vutrisiran, and nedosiran, serving as compelling evidence of the promising potential of RNA interference (RNAi) therapeutics. The successful implementation of siRNA therapeutics is improved through a combination of various chemical modifications and diverse delivery approaches. The utilization of chemically modified siRNA at specific sites on either the sense strand (SS) or antisense strand (AS) has the potential to enhance resistance to ribozyme degradation, improve stability and specificity, and prolong the efficacy of drugs. Herein, we provide comprehensive analyses concerning the correlation between chemical modifications and structure-guided siRNA design. Various modifications, such as 2′-modifications, 2′,4′-dual modifications, non-canonical sugar modifications, and phosphonate mimics, are crucial for the activity of siRNA. We also emphasize the essential strategies for enhancing overhang stability, improving RISC loading efficacy and strand selection, reducing off-target effects, and discussing the future of targeted delivery.

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siRNA 结构引导修饰的进展

迄今为止，美国食品和药物管理局（FDA）已批准了六种小干扰 RNA（siRNA）药物：Patisiran、givosiran、lumasiran、inclisiran、vutrisiran 和 nedosiran，有力地证明了 RNA 干扰（RNAi）疗法的巨大潜力。通过结合各种化学修饰和不同的递送方法，siRNA 疗法的成功应用得到了改善。在有义链（SS）或反义链（AS）上的特定位点利用化学修饰的 siRNA 有可能增强对核糖酶降解的抵抗力，提高稳定性和特异性，并延长药物的疗效。在此，我们全面分析了化学修饰与结构引导 siRNA 设计之间的相关性。各种修饰，如 2′-修饰、2′,4′-双修饰、非经典糖修饰和膦酸盐模拟物，对 siRNA 的活性至关重要。我们还强调了增强悬垂稳定性、提高 RISC 加载效率和链选择、减少脱靶效应的基本策略，并讨论了靶向递送的未来。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.