*Free* Lethal mutagenesis: a viable antiviral strategy with unknown risks

In a Perspective, Ronald Swanstrom and Raymond Schinazi argue that antiviral drugs that lead RNA viruses to produce genetic mutations so fast that they cannot remove deleterious ones – a strategy used in antivirals like the recently approved COVID-19 drug molnupiravir – may be viable, but also present unknown risks to the host. Given the potential for long-term effects, including the possibility of producing variants and the potential for host DNA mutagenesis, the safety of mutagenic drugs needs to be more closely examined, according to the authors. Lethal mutagenesis is an antiviral strategy in which drugs form mutagenic ribonucleosides in host cells that are used in viral RNA replication, introducing errors into the virus’s genetic code, and preventing them from replicating further, eventually driving the invading population to extinction. Several mutagenic drugs have been developed that leverage this approach, including the potent SARS-CoV-2 antiviral molnupiravir. However, according to the authors, there is a knowledge gap between short-term lab-based assays for mutagenic activity and the long-term risks to human health, including related to cancers or reproductive risks, which could take years to become apparent. Swanstrom and Schinazi discuss these risks and how they could be assessed, and provide suggestions on how treatments using lethal mutagenic drugs could be handled moving forward. “Lethal mutagenesis has the potential to be an important antiviral strategy for RNA viruses, especially in emerging infections when there is an absence of virus-specific antivirals,” write Swanstrom and Schinazi. “The potential of this strategy should be exploited, but the possible risks should be acknowledged and addressed.”