Challenges for Targeting SARS-CoV-2 Proteases as a Therapeutic Strategy for COVID-19

Two proteases produced by the SARS-CoV-2 virus, main protease and papain-like protease, are essential for viral replication have become focus of drug development programs treatment COVID-19. We screened a highly focused library compounds containing covalent warheads designed to target cysteine identify new lead scaffolds both Mpro PLpro proteases. These efforts identified small number hits no viable protease. Of as inhibitors purified recombinant only two inhibited infectivity in cellular infection assays. However, we observed substantial drop antiviral potency upon expression TMPRSS2, transmembrane serine that acts an alternative entry pathway lysosomal cathepsins. This loss is explained fact our also potent host cell To determine if this general property inhibitors, evaluated several recently reported found they effective human cathepsins L B showed similar activity cells expressing TMPRSS2. Our results highlight challenges targeting demonstrate need carefully assess selectivity prevent clinical advancement function through inhibition redundant pathway.