Monitoring for SARS-CoV-2 drug resistance mutations in broad viral populations

The search for drugs against COVID-19 and other diseases caused by coronaviruses focuses on the most conserved and essential proteins, mainly the main (Mpro) and the papain-like (PLpro) proteases and the RNA-dependent RNA polymerase (RdRp). Nirmatrelvir, an inhibitor for Mpro, was recently approved by FDA as a part of a two-drug combination, Paxlovid, and many more drugs are in various stages of development. Multiple candidates for the PLpro inhibitors are being studied, but none have yet progressed to clinical trials. Several repurposed inhibitors of RdRp are already in use. We can expect that once anti-COVID-19 drugs become widely used, resistant variants of SARS-CoV-2 will emerge, and we already see that for the drugs targeting SARS-CoV-2 RdRp. We hypothesize that emergence of such variants can be anticipated by identifying possible escape mutations already present in the existing populations of viruses. Our group previously developed the coronavirus3D server (https://coronavirus3d.org), tracking the evolution of SARS-CoV-2 in the context of the three-dimensional structures of its proteins. Here we introduce dedicated pages tracking the emergence of potential drug resistant mutations to Mpro and PLpro, showing that such mutations are already circulating in the SARS-CoV-2 viral population. With regular updates, the drug resistance tracker provides an easy way to monitor and potentially predict the emergence of drug resistance-conferring mutations in the SARS-CoV-2 virus.