In Silico Discovery of Group II Intron RNA Splicing Inhibitors (original) (raw)
ArticlesAugust 21, 2023
In Silico Discovery of Group II Intron RNA Splicing Inhibitors
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- Olga Fedorova
Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520, United States - Grace Arhin
Grace Arhin
Biophysics Program, University of Michigan, Ann Arbor, Michigan 48109, United States - Anna Marie Pyle*
Anna Marie Pyle
Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520, United States
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
*****Email [email protected] - Aaron T. Frank*
Aaron T. Frank
Biophysics Program, University of Michigan, Ann Arbor, Michigan 48109, United States
*****Email: [email protected]
ACS Chemical Biology
Cite this: ACS Chem. Biol. 2023, 18, 9
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Published August 21, 2023
research-article
Copyright © 2023 American Chemical Society
Abstract
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Here, we describe the discovery of compounds that inhibit self-splicing in group II introns. Using docking calculations, we targeted the catalytic active site within the Oceanobacillus iheyensis group IIC intron and virtually screened a library of lead-like compounds. From this initial virtual screen, we identified three unique scaffolds that inhibit splicing in vitro. Additional tests revealed that an analog of the lead scaffold inhibits splicing in an intron-dependent manner. Furthermore, this analog exhibited activity against the group II intron from a different class: the yeast ai5γ IIB intron. The splicing inhibitors we identified could serve as chemical tools for developing group II intron-targeted antifungals, and, more broadly, our results highlight the potential of in silico techniques for identifying bioactive hits against structured and functionally complex RNAs.
ACS Publications
Copyright © 2023 American Chemical Society
Supporting Information
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschembio.3c00160.
The secondary structure of the O.i. group IIC intron; docking studies showing that compound 17 prefers docking to the active-site pocket; structure–activity relationship table of representative O.i. group IIC intron inhibitors (PDF)
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Cited By
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This article is cited by 5 publications.
- Swapnil S. Joshi, Loc T. Huynh, Nidhi Kalia, Gabriel Eaton-Landau, Aaron Aponick, Anna M. Pyle, Michael E. Harris. Assay-Based High Throughput Screening of Diverse Libraries Identifies Selective Inhibitors of Staphylococcus aureus Ribonuclease P. ACS Chemical Biology 2026, Article ASAP.
- Olga Fedorova, Michelle Luo, G. Erik Jagdmann, Jr, Michael C. Van Zandt, Luke Sisto, Anna Marie Pyle. Novel Quinazoline Derivatives Inhibit Splicing of Fungal Group II Introns. ACS Chemical Biology 2025, 20 (2) , 378-385. https://doi.org/10.1021/acschembio.4c00631
- Mengjiao Lv, Jiaqi Fu, Chun Li, Jun Li. Intron RPS25Ai, a Novel DNA Element, Has Global Effects on Synthetic Pathway Engineering by Empowering Protein Synthesis. Journal of Agricultural and Food Chemistry 2024, 72 (51) , 28378-28389. https://doi.org/10.1021/acs.jafc.4c11278
- Yuhan Fei, Pengfei Wang, Jiasheng Zhang, Xinyue Shan, Zilin Cai, Jianbo Ma, Yangming Wang, Qiangfeng Cliff Zhang. Predicting small molecule–RNA interactions without RNA tertiary structures. Nature Biotechnology 2026, 16 https://doi.org/10.1038/s41587-025-02942-z
- Tianshuo Liu, Anna Marie Pyle. Highly Reactive Group I Introns Ubiquitous in Pathogenic Fungi. Journal of Molecular Biology 2024, 436 (8) , 168513. https://doi.org/10.1016/j.jmb.2024.168513
ACS Chemical Biology
Cite this: ACS Chem. Biol. 2023, 18, 9
Click to copy citationCitation copied!
Published August 21, 2023
Copyright © 2023 American Chemical Society
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