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RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays
Tang, Zhichao Zhao, Junxing Pearson, Zach J. Boskovic, Zarko V. Wang, Jingxin
Tang, Zhichao
Zhao, Junxing
Pearson, Zach J.
Boskovic, Zarko V.
Wang, Jingxin
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Abstract
RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered “undruggable” genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers.
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Date
2021-04-14
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MDPI
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Keywords
Alternative splicing, High-throughput screening, Antisense oligonucleotide, Small molecule, Splicing modifier, RNA-targeting
Citation
Tang, Z.; Zhao, J.; Pearson, Z.J.; Boskovic, Z.V.; Wang, J. RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays. Molecules 2021, 26, 2263. https://doi.org/10.3390/molecules26082263