Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity
In RNA viruses, a small increase in their mutation rates can be sufficient to exceed their threshold of viability. Lethal mutagenesis is a therapeutic strategy based on the use of mutagens, driving viral populations to extinction. Extinction catastrophe can be experimentally induced by promutagenic...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/14/4/841 |
| _version_ | 1797408970103586816 |
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| author | Ikbel Hadj Hassine Manel Ben M’hadheb Luis Menéndez-Arias |
| author_facet | Ikbel Hadj Hassine Manel Ben M’hadheb Luis Menéndez-Arias |
| author_sort | Ikbel Hadj Hassine |
| collection | DOAJ |
| description | In RNA viruses, a small increase in their mutation rates can be sufficient to exceed their threshold of viability. Lethal mutagenesis is a therapeutic strategy based on the use of mutagens, driving viral populations to extinction. Extinction catastrophe can be experimentally induced by promutagenic nucleosides in cell culture models. The loss of HIV infectivity has been observed after passage in 5-hydroxydeoxycytidine or 5,6-dihydro-5-aza-2′-deoxycytidine while producing a two-fold increase in the viral mutation frequency. Among approved nucleoside analogs, experiments with polioviruses and other RNA viruses suggested that ribavirin can be mutagenic, although its mechanism of action is not clear. Favipiravir and molnupiravir exert an antiviral effect through lethal mutagenesis. Both drugs are broad-spectrum antiviral agents active against RNA viruses. Favipiravir incorporates into viral RNA, affecting the G→A and C→U transition rates. Molnupiravir (a prodrug of β-<span style="font-variant: small-caps;">d</span>-N<sup>4</sup>-hydroxycytidine) has been recently approved for the treatment of SARS-CoV-2 infection. Its triphosphate derivative can be incorporated into viral RNA and extended by the coronavirus RNA polymerase. Incorrect base pairing and inefficient extension by the polymerase promote mutagenesis by increasing the G→A and C→U transition frequencies. Despite having remarkable antiviral action and resilience to drug resistance, carcinogenic risks and genotoxicity are important concerns limiting their extended use in antiviral therapy. |
| first_indexed | 2024-03-09T04:06:22Z |
| format | Article |
| id | doaj.art-33636d5fa87942abac43093c22964937 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T04:06:22Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-33636d5fa87942abac43093c229649372023-12-03T14:04:47ZengMDPI AGViruses1999-49152022-04-0114484110.3390/v14040841Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic ActivityIkbel Hadj Hassine0Manel Ben M’hadheb1Luis Menéndez-Arias2Unité de Recherche UR17ES30 “Génomique, Biotechnologie et Stratégies Antivirales”, Institut Supérieur de Biotechnologie, Université de Monastir, Monastir 5000, TunisiaUnité de Recherche UR17ES30 “Génomique, Biotechnologie et Stratégies Antivirales”, Institut Supérieur de Biotechnologie, Université de Monastir, Monastir 5000, TunisiaCentro de Biología Molecular “Severo Ochoa” (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), 28049 Madrid, SpainIn RNA viruses, a small increase in their mutation rates can be sufficient to exceed their threshold of viability. Lethal mutagenesis is a therapeutic strategy based on the use of mutagens, driving viral populations to extinction. Extinction catastrophe can be experimentally induced by promutagenic nucleosides in cell culture models. The loss of HIV infectivity has been observed after passage in 5-hydroxydeoxycytidine or 5,6-dihydro-5-aza-2′-deoxycytidine while producing a two-fold increase in the viral mutation frequency. Among approved nucleoside analogs, experiments with polioviruses and other RNA viruses suggested that ribavirin can be mutagenic, although its mechanism of action is not clear. Favipiravir and molnupiravir exert an antiviral effect through lethal mutagenesis. Both drugs are broad-spectrum antiviral agents active against RNA viruses. Favipiravir incorporates into viral RNA, affecting the G→A and C→U transition rates. Molnupiravir (a prodrug of β-<span style="font-variant: small-caps;">d</span>-N<sup>4</sup>-hydroxycytidine) has been recently approved for the treatment of SARS-CoV-2 infection. Its triphosphate derivative can be incorporated into viral RNA and extended by the coronavirus RNA polymerase. Incorrect base pairing and inefficient extension by the polymerase promote mutagenesis by increasing the G→A and C→U transition frequencies. Despite having remarkable antiviral action and resilience to drug resistance, carcinogenic risks and genotoxicity are important concerns limiting their extended use in antiviral therapy.https://www.mdpi.com/1999-4915/14/4/841lethal mutagenesiserror catastrophenucleoside analogsribavirinfavipiravirmolnupiravir |
| spellingShingle | Ikbel Hadj Hassine Manel Ben M’hadheb Luis Menéndez-Arias Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity Viruses lethal mutagenesis error catastrophe nucleoside analogs ribavirin favipiravir molnupiravir |
| title | Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity |
| title_full | Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity |
| title_fullStr | Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity |
| title_full_unstemmed | Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity |
| title_short | Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity |
| title_sort | lethal mutagenesis of rna viruses and approved drugs with antiviral mutagenic activity |
| topic | lethal mutagenesis error catastrophe nucleoside analogs ribavirin favipiravir molnupiravir |
| url | https://www.mdpi.com/1999-4915/14/4/841 |
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