Lethal mutagenesis as an antiviral strategy

Abstract: VIEWPOINT: COVID-19 Lethal mutagenesis as an antiviral strategy Lethal mutagenesis of RNA viruses is a viable antiviral strategy but has unknown risks By Ronald Swanstrom1 and Raymond F. Schinazi2 V 1 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 2 Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA. Email: risunc@med.unc.edu SCIENCE science.org based assay, NHC was 100 times more potent as an inhibitor of SARS-CoV-2 than ribavirin or favipiravir (13). Molnupiravir was efficacious in mouse models of respiratory SARSCoV and Middle East respiratory syndrome coronavirus (MERS-CoV) infection (9), consistent with NHC having broad antiviral activity (10). A recently reported clinical trial of molnupiravir showed a 30% reduction in hospitalization when people with symptomatic SARS-CoV-2 infection (and at risk for more serious disease) were treated with molnupiravir within the first 5 days of symptoms (14). Based on these results, the US Food and Drug Administration (FDA) has approved an emergency use authorization (EUA) for molnupiravir to treat symptomatic SARS-CoV-2 infections. Molnupiravir has also been approved for the treatment of COVID-19 in the United Kingdom, and there are expectations that it will be made widely available around the world. However, the antiviral strategy of lethal mutagenesis comes with a cautionary note. Ribonucleosides must be phosphorylated to the 59-triphosphate form to be substrates for RNA synthesis (host or viral). Ribonucleosides synthesized by the host cell are formed as the 59-monophosphate. Ribonucleoside analogs enter this biosynthetic pathway through phosphorylation by a salvage kinase to form the 59-monophosphate (see the figure). The ribonucleoside 59-monophosphate is phosphorylated to the ribonucleoside 59-diphosphate and then to the 59-triphosphate (now ready for RNA synthesis). The ribonucleoside 59-diphosphate is the obligatory intermediate in this pathway, which creates a potential problem. Ribonucleoside 59-diphosphate is also the obligatory intermediate in the synthesis of the 29-deoxyribonucleoside 59-diphosphate that is on the pathway to form 29-deoxyribonucleoside 59-triphosphates, which are used in DNA synthesis. The enzyme ribonucleotide reductase (RNR) is responsible for this reaction. Thus, there is a clear metabolic pathway for a mutagenic ribonucleoside analog to become a precursor for host DNA synthesis. Molnupiravir was shown to be positive in the bacterial Ames test (an assay that measures mutagenic potential), where two animal model assays of mutagenic potential were largely negative, leading the FDA to state in the EUA fact sheet that “molnupiravir is low 4 FEBRUARY 2022 • VOL 375 ISSUE 6580 497 iruses depend on the host cell to carry out much of their replication, with each offering only a few virus-specific targets for the development of antiviral therapies. This makes the development of broadly active antivirals difficult to conceptualize. Numerous RNA viruses—including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus, and Chikungunya virus—have led to recent epidemics, highlighting the need for effective antiviral drugs that can be enlisted quickly. Some years ago, a broadly applicable antiviral strategy was proposed in..