An epimer of threose nucleic acid enhances oligonucleotide exonuclease resistance through end capping
Abstract End capping of oligonucleotides by modified nucleotides is essential for boosting resistance to 3’ exonuclease degradation, thereby enhancing their stability and therapeutic efficacy in vivo. However, the rationale behind these modifications remains unclear. In this study, we designed a nov...
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Nature Portfolio
2025-05-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01545-8 |
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| author | Junlin Wen Chunlei Zhang Xue Chen Ziwen Dai Mengting Li Wenjian Ma ChiYung Yam Xiaoluo Huang Chenghe Xiong Hui Mei |
| author_facet | Junlin Wen Chunlei Zhang Xue Chen Ziwen Dai Mengting Li Wenjian Ma ChiYung Yam Xiaoluo Huang Chenghe Xiong Hui Mei |
| author_sort | Junlin Wen |
| collection | DOAJ |
| description | Abstract End capping of oligonucleotides by modified nucleotides is essential for boosting resistance to 3’ exonuclease degradation, thereby enhancing their stability and therapeutic efficacy in vivo. However, the rationale behind these modifications remains unclear. In this study, we designed a novel nucleic acid analog, eTNA, by replacing deoxyribose with the α-D-erythrofuranosyl moiety. As an epimer of TNA (threose nucleic acid), it combines structural features from inverted-dT and TNA, both known for enhancing resistance against 3’-exonucleases. On top of this, we systematically investigated the stability of a series of oligonucleotides capped with inverted-dT, TNA and eTNA at the 5’-, 3’-, or both ends. The structural differences between eTNA and natural dT help to understand how the sugar ring’s conformation and rigidity affect duplex stability and exonuclease resistance. Our experimental and theoretical results show that the modified furanose affects the binding positions of terminal nucleotides in the phosphodiesterase active site, preventing phosphodiester hydrolysis. Our mechanistic study should benefit future therapeutic oligonucleotide design with end capping. |
| format | Article |
| id | doaj-art-d7a0a2a6f2ca4356b6e9f6f831cca0fc |
| institution | DOAJ |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-d7a0a2a6f2ca4356b6e9f6f831cca0fc2025-08-20T03:10:18ZengNature PortfolioCommunications Chemistry2399-36692025-05-018111210.1038/s42004-025-01545-8An epimer of threose nucleic acid enhances oligonucleotide exonuclease resistance through end cappingJunlin Wen0Chunlei Zhang1Xue Chen2Ziwen Dai3Mengting Li4Wenjian Ma5ChiYung Yam6Xiaoluo Huang7Chenghe Xiong8Hui Mei9Shenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesGingko Biotech LimitedShenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesShenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesShenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesCollege of Biotechnology, Tianjin University of Science and TechnologyShenzhen Institute for Advanced Study, University of Electronic Science and Technology of ChinaShenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesShenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesShenzhen Key Laboratory of Synthetic Genomics, Guangdong Provincial Key Laboratory of Synthetic Genomics, State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesAbstract End capping of oligonucleotides by modified nucleotides is essential for boosting resistance to 3’ exonuclease degradation, thereby enhancing their stability and therapeutic efficacy in vivo. However, the rationale behind these modifications remains unclear. In this study, we designed a novel nucleic acid analog, eTNA, by replacing deoxyribose with the α-D-erythrofuranosyl moiety. As an epimer of TNA (threose nucleic acid), it combines structural features from inverted-dT and TNA, both known for enhancing resistance against 3’-exonucleases. On top of this, we systematically investigated the stability of a series of oligonucleotides capped with inverted-dT, TNA and eTNA at the 5’-, 3’-, or both ends. The structural differences between eTNA and natural dT help to understand how the sugar ring’s conformation and rigidity affect duplex stability and exonuclease resistance. Our experimental and theoretical results show that the modified furanose affects the binding positions of terminal nucleotides in the phosphodiesterase active site, preventing phosphodiester hydrolysis. Our mechanistic study should benefit future therapeutic oligonucleotide design with end capping.https://doi.org/10.1038/s42004-025-01545-8 |
| spellingShingle | Junlin Wen Chunlei Zhang Xue Chen Ziwen Dai Mengting Li Wenjian Ma ChiYung Yam Xiaoluo Huang Chenghe Xiong Hui Mei An epimer of threose nucleic acid enhances oligonucleotide exonuclease resistance through end capping Communications Chemistry |
| title | An epimer of threose nucleic acid enhances oligonucleotide exonuclease resistance through end capping |
| title_full | An epimer of threose nucleic acid enhances oligonucleotide exonuclease resistance through end capping |
| title_fullStr | An epimer of threose nucleic acid enhances oligonucleotide exonuclease resistance through end capping |
| title_full_unstemmed | An epimer of threose nucleic acid enhances oligonucleotide exonuclease resistance through end capping |
| title_short | An epimer of threose nucleic acid enhances oligonucleotide exonuclease resistance through end capping |
| title_sort | epimer of threose nucleic acid enhances oligonucleotide exonuclease resistance through end capping |
| url | https://doi.org/10.1038/s42004-025-01545-8 |
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