A strategy for evaluating potential antiviral resistance to small molecule drugs and application to SARS-CoV-2

Alterations in viral fitness cannot be inferred from only mutagenesis studies of an isolated viral protein. To-date, no systematic analysis has been performed to identify mutations that improve virus fitness and reduce drug efficacy. We present a generic strategy to evaluate which viral mutations might diminish drug efficacy and applied it to assess how SARS-CoV-2 evolution may affect the efficacy of current approved/candidate small-molecule antivirals for M-pro, PLpro, and RdRp. For each drug target, we determined the drug-interacting virus residues from available structures and the selection pressure of the virus residues from the SARS-CoV-2 genomes. This enabled the identification of promising drug target regions and small-molecule antivirals that the virus can develop resistance. Our strategy of utilizing sequence and structural information from genomic sequence and protein structure databanks can rapidly assess the fitness of any emerging virus variants and can aid antiviral drug design for future pathogens.

Automated summary

Inferences about viral fitness cannot be made solely from mutagenesis studies of an isolated viral protein. A systematic analysis is lacking in identifying mutations that enhance virus fitness while reducing drug effectiveness. This study presents a general strategy to identify viral mutations that may decrease the efficacy of antiviral drugs targeting M-pro, PLpro, and RdRp in SARS-CoV-2. By analyzing drug-interacting virus residues and selection pressure of virus residues, potential drug target regions and antiviral resistance can be identified. This strategy utilizing genomic sequence and protein structure databases can quickly assess the fitness of emerging virus variants and guide future antiviral drug design.