β-d-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells

Abstract

Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in the genomes of RNA viruses during viral replication. β-D-N 4-hydroxycytidine (NHC, the initial metabolite of molnupiravir) is more than 100-fold more active than ribavirin or favipiravir against SARS-CoV-2, with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate that highly active mutagenic ribonucleosides may hold risk for the host.

Molnupiravir in COVID-19: A systematic review of literature

“…From the safety perspective, theoretically, while its mutagenic potential on one hand is a boon for reducing the viral RNA, it might turn into a bane by inducing mutations in the virus further leading to an increased resistance. At least one study [ 9 ] in animal cell cultures found mutations in cells treated with molnupiravir and recommends to assess mutagenic potential and potential genotoxic side effects in vivo , focusing on rapidly dividing cells. Skepticism about safety still remains given the fact that the participants in the trial had to maintain abstinence or use contraception for the fear of birth defect if they conceived.…”

“…1 illustrates the mechanism of action (schematic representation) of molnupiravir against SARS-CoV-2 and its comparison with remdesivir and favipiravir. These mutations are also produced in the host cell (mammalian DNA) which raises concerns regarding its interference with vaccination, and its potential carcinogenic and teratogenic effects which are theoretically possible with mutagenic drugs [ 9 ]. However, it might be less likely because of its proposed short-term use – twice daily for 5 days.…”

Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19

“…The viricidal effect of molnupiravir is due to its mutagenic effects in the virus, wherein RdRp utilizes the active triphosphate form of molnupiravir (EIDD-2061, Figure 1C) as a substrate in place of cytidine/uridine triphosphate and generates mutated RNA copies [56]. A report states that active ribonucleosides, including molnupiravir, may also be mutagenic to the host [57]. However, another report mentions that molnupiravir has a sound safety profile [58].…”

Decoding molnupiravir-induced mutagenesis in SARS-CoV-2

“…Approved in Japan for the treatment of influenza, favipiravir is also licensed in China and Russia for COVID-19 treatment. A recent study by Zhou et al (10) showed that NHC is more than 100-fold more active than ribavirin and favipiravir against SARS-CoV-2, while the observed activity correlated with an increased mutation frequency in the viral RNA. It would be interesting to see whether the methodological approach of Gordon et al (8) could throw some light on the potential mechanism of action of favipiravir in the context of SARS-CoV-2 and influenza virus infections.…”

“…NHC can be metabolized by the host cell to the 2´-deoxyribonucleoside form by the ribonucleotide reductase and then incorporated into the host cell DNA. The mutagenic effect of NHC has been shown in animal cell cultures (10), raising concerns on the potential risk of molnupiravir-induced tumorigenesis, and the emergence of detrimental mutations in sperm precursor cell generation and embryo development.…”