Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA
The SARS-CoV-2 betacoronavirus pandemic has claimed more than 6.5 million lives and, despite the development and use of COVID-19 vaccines, remains a major global public health problem. The development of specific drugs for the treatment of this disease remains a very urgent task. In the context of a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3361 |
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| author | Elena Matyugina Ivan Petushkov Sergei Surzhikov Vasily Kezin Anna Maslova Olga Ivanova Olga Smirnova Ilya Kirillov Irina Fedyakina Andrey Kulbachinskiy Sergey Kochetkov Anastasia Khandazhinskaya |
| author_facet | Elena Matyugina Ivan Petushkov Sergei Surzhikov Vasily Kezin Anna Maslova Olga Ivanova Olga Smirnova Ilya Kirillov Irina Fedyakina Andrey Kulbachinskiy Sergey Kochetkov Anastasia Khandazhinskaya |
| author_sort | Elena Matyugina |
| collection | DOAJ |
| description | The SARS-CoV-2 betacoronavirus pandemic has claimed more than 6.5 million lives and, despite the development and use of COVID-19 vaccines, remains a major global public health problem. The development of specific drugs for the treatment of this disease remains a very urgent task. In the context of a repurposing strategy, we previously screened a library of nucleoside analogs showing different types of biological activity against the SARS-CoV-2 virus. The screening revealed compounds capable of inhibiting the reproduction of SARS-CoV-2 with EC<sub>50</sub> values in the range of 20–50 µM. Here we present the design and synthesis of various analogs of the leader compounds, the evaluation of their cytotoxicity and antiviral activity against SARS-CoV-2 in cell cultures, as well as experimental data on RNA-dependent RNA polymerase inhibition. Several compounds have been shown to prevent the interaction between the SARS-CoV-2 RNA-dependent RNA polymerase and the RNA substrate, likely inhibiting virus replication. Three of the synthesized compounds have also been shown to inhibit influenza virus. The structures of these compounds can be used for further optimization in order to develop an antiviral drug. |
| first_indexed | 2024-03-11T08:43:48Z |
| format | Article |
| id | doaj.art-4305aeb0db2e468789bf9d0226265656 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:43:48Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4305aeb0db2e468789bf9d02262656562023-11-16T20:58:54ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244336110.3390/ijms24043361Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNAElena Matyugina0Ivan Petushkov1Sergei Surzhikov2Vasily Kezin3Anna Maslova4Olga Ivanova5Olga Smirnova6Ilya Kirillov7Irina Fedyakina8Andrey Kulbachinskiy9Sergey Kochetkov10Anastasia Khandazhinskaya11Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaInstitute of Molecular Genetics, National Research Center “Kurchatov Institute”, 123182 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaGamaleya National Research Center for Epidemiology and Microbiology, Russian Ministry of Health, 123098 Moscow, RussiaGamaleya National Research Center for Epidemiology and Microbiology, Russian Ministry of Health, 123098 Moscow, RussiaInstitute of Molecular Genetics, National Research Center “Kurchatov Institute”, 123182 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaThe SARS-CoV-2 betacoronavirus pandemic has claimed more than 6.5 million lives and, despite the development and use of COVID-19 vaccines, remains a major global public health problem. The development of specific drugs for the treatment of this disease remains a very urgent task. In the context of a repurposing strategy, we previously screened a library of nucleoside analogs showing different types of biological activity against the SARS-CoV-2 virus. The screening revealed compounds capable of inhibiting the reproduction of SARS-CoV-2 with EC<sub>50</sub> values in the range of 20–50 µM. Here we present the design and synthesis of various analogs of the leader compounds, the evaluation of their cytotoxicity and antiviral activity against SARS-CoV-2 in cell cultures, as well as experimental data on RNA-dependent RNA polymerase inhibition. Several compounds have been shown to prevent the interaction between the SARS-CoV-2 RNA-dependent RNA polymerase and the RNA substrate, likely inhibiting virus replication. Three of the synthesized compounds have also been shown to inhibit influenza virus. The structures of these compounds can be used for further optimization in order to develop an antiviral drug.https://www.mdpi.com/1422-0067/24/4/3361antiviral activitycarbocyclic and acyclic analogs of nucleosides6-substituted derivatives of 3H-pyrrolo [2,3-d]-pyrimidine-2-oneinhibitorsSARS-CoV-2 RNA-dependent RNA polymeraseinfluenza virus |
| spellingShingle | Elena Matyugina Ivan Petushkov Sergei Surzhikov Vasily Kezin Anna Maslova Olga Ivanova Olga Smirnova Ilya Kirillov Irina Fedyakina Andrey Kulbachinskiy Sergey Kochetkov Anastasia Khandazhinskaya Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA International Journal of Molecular Sciences antiviral activity carbocyclic and acyclic analogs of nucleosides 6-substituted derivatives of 3H-pyrrolo [2,3-d]-pyrimidine-2-one inhibitors SARS-CoV-2 RNA-dependent RNA polymerase influenza virus |
| title | Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA |
| title_full | Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA |
| title_fullStr | Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA |
| title_full_unstemmed | Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA |
| title_short | Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA |
| title_sort | nucleoside analogs that inhibit sars cov 2 replication by blocking interaction of virus polymerase with rna |
| topic | antiviral activity carbocyclic and acyclic analogs of nucleosides 6-substituted derivatives of 3H-pyrrolo [2,3-d]-pyrimidine-2-one inhibitors SARS-CoV-2 RNA-dependent RNA polymerase influenza virus |
| url | https://www.mdpi.com/1422-0067/24/4/3361 |
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