Biochemistry-informed design selects potent siRNAs against SARS-CoV-2
RNA interference (RNAi) offers an efficient way to repress genes of interest, and it is widely used in research settings. Clinical applications emerged more recently, with 5 approved siRNAs (the RNA guides of the RNAi effector complex) against human diseases. The development of siRNAs against the SA...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | RNA Biology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15476286.2023.2217400 |
| _version_ | 1797403978685743104 |
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| author | Élisabeth Houbron Sophie Mockly Sophia Rafasse Nathalie Gros Delphine Muriaux Hervé Seitz |
| author_facet | Élisabeth Houbron Sophie Mockly Sophia Rafasse Nathalie Gros Delphine Muriaux Hervé Seitz |
| author_sort | Élisabeth Houbron |
| collection | DOAJ |
| description | RNA interference (RNAi) offers an efficient way to repress genes of interest, and it is widely used in research settings. Clinical applications emerged more recently, with 5 approved siRNAs (the RNA guides of the RNAi effector complex) against human diseases. The development of siRNAs against the SARS-CoV-2 virus could therefore provide the basis of novel COVID-19 treatments, while being easily adaptable to future variants or to other, unrelated viruses. Because the biochemistry of RNAi is very precisely described, it is now possible to design siRNAs with high predicted activity and specificity using only computational tools. While previous siRNA design algorithms tended to rely on simplistic strategies (raising fully complementary siRNAs against targets of interest), our approach uses the most up-to-date mechanistic description of RNAi to allow mismatches at tolerable positions and to force them at beneficial positions, while optimizing siRNA duplex asymmetry. Our pipeline proposes 8 siRNAs against SARS-CoV-2, and ex vivo assessment confirms the high antiviral activity of 6 out of 8 siRNAs, also achieving excellent variant coverage (with several 3-siRNA combinations recognizing each correctly-sequenced variant as of September 2022). Our approach is easily generalizable to other viruses as long as a variant genome database is available. With siRNA delivery procedures being currently improved, RNAi could therefore become an efficient and versatile antiviral therapeutic strategy. |
| first_indexed | 2024-03-09T02:46:24Z |
| format | Article |
| id | doaj.art-92e2bdd2d7e847c691e930adad7d4420 |
| institution | Directory Open Access Journal |
| issn | 1547-6286 1555-8584 |
| language | English |
| last_indexed | 2024-03-09T02:46:24Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | RNA Biology |
| spelling | doaj.art-92e2bdd2d7e847c691e930adad7d44202023-12-05T16:09:52ZengTaylor & Francis GroupRNA Biology1547-62861555-85842023-12-0120127228010.1080/15476286.2023.22174002217400Biochemistry-informed design selects potent siRNAs against SARS-CoV-2Élisabeth Houbron0Sophie Mockly1Sophia Rafasse2Nathalie Gros3Delphine Muriaux4Hervé Seitz5UMR 9002 CNRS and University of MontpellierUMR 9002 CNRS and University of MontpellierCEMIPAI UAR 3725 CNRS and University of MontpellierCEMIPAI UAR 3725 CNRS and University of MontpellierCEMIPAI UAR 3725 CNRS and University of MontpellierUMR 9002 CNRS and University of MontpellierRNA interference (RNAi) offers an efficient way to repress genes of interest, and it is widely used in research settings. Clinical applications emerged more recently, with 5 approved siRNAs (the RNA guides of the RNAi effector complex) against human diseases. The development of siRNAs against the SARS-CoV-2 virus could therefore provide the basis of novel COVID-19 treatments, while being easily adaptable to future variants or to other, unrelated viruses. Because the biochemistry of RNAi is very precisely described, it is now possible to design siRNAs with high predicted activity and specificity using only computational tools. While previous siRNA design algorithms tended to rely on simplistic strategies (raising fully complementary siRNAs against targets of interest), our approach uses the most up-to-date mechanistic description of RNAi to allow mismatches at tolerable positions and to force them at beneficial positions, while optimizing siRNA duplex asymmetry. Our pipeline proposes 8 siRNAs against SARS-CoV-2, and ex vivo assessment confirms the high antiviral activity of 6 out of 8 siRNAs, also achieving excellent variant coverage (with several 3-siRNA combinations recognizing each correctly-sequenced variant as of September 2022). Our approach is easily generalizable to other viruses as long as a variant genome database is available. With siRNA delivery procedures being currently improved, RNAi could therefore become an efficient and versatile antiviral therapeutic strategy.http://dx.doi.org/10.1080/15476286.2023.2217400sirnarnaisars-cov-2sirna designrna accessibility |
| spellingShingle | Élisabeth Houbron Sophie Mockly Sophia Rafasse Nathalie Gros Delphine Muriaux Hervé Seitz Biochemistry-informed design selects potent siRNAs against SARS-CoV-2 RNA Biology sirna rnai sars-cov-2 sirna design rna accessibility |
| title | Biochemistry-informed design selects potent siRNAs against SARS-CoV-2 |
| title_full | Biochemistry-informed design selects potent siRNAs against SARS-CoV-2 |
| title_fullStr | Biochemistry-informed design selects potent siRNAs against SARS-CoV-2 |
| title_full_unstemmed | Biochemistry-informed design selects potent siRNAs against SARS-CoV-2 |
| title_short | Biochemistry-informed design selects potent siRNAs against SARS-CoV-2 |
| title_sort | biochemistry informed design selects potent sirnas against sars cov 2 |
| topic | sirna rnai sars-cov-2 sirna design rna accessibility |
| url | http://dx.doi.org/10.1080/15476286.2023.2217400 |
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