Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5’ untranslated region
Abstract One of the hallmarks of RNA viruses is highly structured untranslated regions (UTRs) which are often essential for viral replication, transcription, or translation. In this report, we discovered a series of coumarin derivatives that bind to a four-way RNA helix called SL5 in the 5’ UTR of t...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55608-w |
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| author | Zhichao Tang Shalakha Hegde Siyuan Hao Manikandan Selvaraju Jianming Qiu Jingxin Wang |
| author_facet | Zhichao Tang Shalakha Hegde Siyuan Hao Manikandan Selvaraju Jianming Qiu Jingxin Wang |
| author_sort | Zhichao Tang |
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| description | Abstract One of the hallmarks of RNA viruses is highly structured untranslated regions (UTRs) which are often essential for viral replication, transcription, or translation. In this report, we discovered a series of coumarin derivatives that bind to a four-way RNA helix called SL5 in the 5’ UTR of the SARS-CoV-2 RNA genome. To locate the binding site, we developed a sequencing-based method namely cgSHAPE-seq, in which an acylating probe was directed to crosslink with the 2’-OH group of ribose at the binding site to create read-through mutations during reverse transcription. cgSHAPE-seq unambiguously determined a bulged G in SL5 as the primary binding site, which was validated through mutagenesis and in vitro binding experiments. The coumarin derivatives were further used as a warhead in designing RNA-degrading chimeras to reduce viral RNA expression levels. The optimized RNA-degrading chimera C64 inhibited live virus replication in lung epithelial carcinoma cells. |
| format | Article |
| id | doaj-art-a60e5571e6884f2ab92a8b921e11c7e6 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a60e5571e6884f2ab92a8b921e11c7e62025-01-12T12:29:55ZengNature PortfolioNature Communications2041-17232025-01-0116111110.1038/s41467-024-55608-wChemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5’ untranslated regionZhichao Tang0Shalakha Hegde1Siyuan Hao2Manikandan Selvaraju3Jianming Qiu4Jingxin Wang5Department of Medicinal Chemistry, University of KansasDepartment of Medicinal Chemistry, University of KansasDepartment of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical CenterDepartment of Medicinal Chemistry, University of KansasDepartment of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical CenterDepartment of Medicinal Chemistry, University of KansasAbstract One of the hallmarks of RNA viruses is highly structured untranslated regions (UTRs) which are often essential for viral replication, transcription, or translation. In this report, we discovered a series of coumarin derivatives that bind to a four-way RNA helix called SL5 in the 5’ UTR of the SARS-CoV-2 RNA genome. To locate the binding site, we developed a sequencing-based method namely cgSHAPE-seq, in which an acylating probe was directed to crosslink with the 2’-OH group of ribose at the binding site to create read-through mutations during reverse transcription. cgSHAPE-seq unambiguously determined a bulged G in SL5 as the primary binding site, which was validated through mutagenesis and in vitro binding experiments. The coumarin derivatives were further used as a warhead in designing RNA-degrading chimeras to reduce viral RNA expression levels. The optimized RNA-degrading chimera C64 inhibited live virus replication in lung epithelial carcinoma cells.https://doi.org/10.1038/s41467-024-55608-w |
| spellingShingle | Zhichao Tang Shalakha Hegde Siyuan Hao Manikandan Selvaraju Jianming Qiu Jingxin Wang Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5’ untranslated region Nature Communications |
| title | Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5’ untranslated region |
| title_full | Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5’ untranslated region |
| title_fullStr | Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5’ untranslated region |
| title_full_unstemmed | Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5’ untranslated region |
| title_short | Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5’ untranslated region |
| title_sort | chemical guided shape sequencing cgshape seq informs the binding site of rna degrading chimeras targeting sars cov 2 5 untranslated region |
| url | https://doi.org/10.1038/s41467-024-55608-w |
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