Recent changes in the mutational dynamics of the SARS-CoV-2 main-protease substantiate the danger of emerging resistance to antiviral drugs.

Abstract The current COVID-19 pandemic poses a challenge to medical professionals and the general public alike. In addition to vaccination programs and nontherapeutic measures being employed worldwide to encounter SARS-CoV-2, great efforts have been made towards drug development and evaluation. In particular, the main protease (Mpro) makes an attractive drug target due to its high level characterization and relatively little similarity to host proteases. Essentially, antiviral strategies are vulnerable to the effects of viral mutation and an early detection of arising resistances supports a timely counteraction in drug development and deployment. Here we show a significant recent event of mutational dynamics in Mpro. Although the protease has a priori been expected to be relatively conserved, we report a remarkable increase in mutational variability in an eight-residue long consecutive region near the active site since December 2021. The location of this event in close proximity to an antiviral-drug binding site may suggest the onset of the development of antiviral resistance. Our findings emphasize the importance of monitoring the mutational dynamics of Mpro together with possible consequences arising from amino-acid exchanges emerging in regions critical with regard to the susceptibility of the virus to antivirals targeting the protease.