Mikutis Sigitas, Bernardes Gonçalo J L
Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
Chem Rev. 2024 Dec 11;124(23):13301-13330. doi: 10.1021/acs.chemrev.4c00472. Epub 2024 Nov 5.
The vast majority of the human genome codes for RNA, but RNA-targeting therapeutics account for a small fraction of approved drugs. As such, there is great incentive to improve old and develop new approaches to RNA targeting. For many RNA targeting modalities, just binding is not sufficient to exert a therapeutic effect; thus, targeted RNA degradation and induced decay emerged as powerful approaches with a pronounced biological effect. This review covers the origins and advanced use cases of targeted RNA degrader technologies grouped by the nature of the targeting modality as well as by the mode of degradation. It covers both well-established methods and clinically successful platforms such as RNA interference, as well as emerging approaches such as recruitment of RNA quality control machinery, CRISPR, and direct targeted RNA degradation. We also share our thoughts on the biggest hurdles in this field, as well as possible ways to overcome them.
人类基因组的绝大部分编码RNA，但靶向RNA的治疗药物在获批药物中只占一小部分。因此，改进旧方法并开发新的RNA靶向方法具有很大的吸引力。对于许多RNA靶向方式而言，仅仅结合不足以发挥治疗作用；因此，靶向RNA降解和诱导衰变成为具有显著生物学效应的强大方法。本综述涵盖了靶向RNA降解技术的起源和先进应用案例，这些技术按靶向方式的性质以及降解模式进行分类。它涵盖了成熟的方法和临床成功的平台，如RNA干扰，以及新兴的方法，如招募RNA质量控制机制、CRISPR和直接靶向RNA降解。我们还分享了我们对该领域最大障碍以及克服这些障碍的可能方法的看法。
