The ambiguous base-pairing of rNHC after incorporation places it in the class of mutagenic compounds targeting incorporation into viral RNA (along with favipiravir [FAV], a base analog [6], and ribavirin [RBV], a ribonucleoside analog [7]). Here we considered the antiviral activity against SARS-CoV-2 of rNHC, FAV, and RBV in a head-to-head comparison of viral inhibition and the ability to induce mutations in the viral genome. Due to their mechanism of action, mutagenic ribonucleoside analogs could be metabolized by the host cell to the 2'-deoxyribonucleotide form by ribonucleotide reductase and then incorporated into DNA, leading to mutagenesis of the host. Thus, we also examined mutagenesis of host DNA using a modified hypoxanthine phosphoribosyltransferase (HPRT) gene mutation assay [8]. We found that rNHC has potent antiviral activity far beyond FAV and RBV but is also mutagenic to the host in the HPRT mutagenesis assay.
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