Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity

Abstract

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-d-N4-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.

SARS‐CoV‐2 Non-structural protein 1(NSP1) mutation virulence and natural selection: Evolutionary trends in the six continents

“…According to the high percentage of no mutant regions on NSP1 AASs in all geographical areas, the data demonstrate NSP1 as a conserved region that was preserved against a high replication and high mutation rate allowing RNA viruses to escape the immune system during the evolution ( Hadj Hassine et al., 2022 ). The mutation frequency was determined based on the number of mutations in each segment relative to the total mass.…”

“…The noticed change can affect the replication rate and preferential expression of viral RNA in the infected cell and increase them. The E102K mutation that reported as the top mutation in Africa, was founded in the Tanzanian variant ( Hadj Hassine et al., 2022 ).…”

Atypical Mutational Spectrum of SARS-CoV-2 Replicating in the Presence of Ribavirin

“…Experimental proof of the concept was provided by showing the detrimental effect on RNA virus survival of replication in the presence of mutagenic agents ( 7 – 11 ). To date, at least 25 different RNA viruses have been suppressed or extinguished in cell culture or in vivo assays by base and nucleoside analogues, which exert at least part of their antiviral activity through viral mutagenesis by the corresponding nucleoside-triphosphates (examples of specific studies in references 12 to 15 ; recent reviews in references 16 and 17 ).…”

Evolutionary models predict potential mechanisms of escape from mutational meltdown

“…Several examples of adaptation of RNA viruses to mutagenic drugs have been reported (reviewed in (24).…”

“…Nevertheless, several examples of mutagenic drug resistance in RNA viruses have been reported (reviewed in (24). For example, rivabirin resistance was observed in-vitro in poliovirus and patient hepatitis C virus strains (25, 26), whereas remdesivir was shown to induce resistance in in-vitro Sars-CoV-2 (27).…”