Identification of potential targets against SARS-CoV-2 of antiviral drugs based on photoaffinity probes

Facing the sudden outbreak of coronavirus disease 2019 (COVID-19), it is extremely urgent to develop effective antiviral drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Drug repurposing is a promising strategy for the treatment of COVID-19. To identify the precise target protein of marketed medicines, we initiate a chemical biological program to identify precise target of potential antivirus drugs. In this study, two types of recombinant human coronavirus SARS-CoV-2 RdRp protein capturing probes with various photoaffinity labeling units were designed and synthesized based on the structure of FDA-approved drugs stavudine, remdesivir, acyclovir, and aladenosine. Fortunately, it was found that one novel photoaffinity probe, RD-1, could diaplayed good affinity with SARS-CoV-2 RdRp around the residue ARG_553. In addition, RD-1 probe also exhibited potent inhibitory activity against 3CL^pro protease. Taken together, our findings will elucidate the structural basis for the efficacy of marketed drugs, and explore a rapid and efficient strategy of drug repurposing based on the identification of new targets. Moreover, these results could also provide a scientific basis for the clinical application of marketed drugs.