Au(I)-based compounds inhibit nsp14/nsp10 and nsp13 (helicase) to exert anti-SARS-CoV-2 properties

Au(I) compounds have long been associated with medicine for the treatment of various diseases, especially auranofin has been used for the treatment of rheumatoid arthritis. In addition, Au(I) based compounds also exhibit anti-cancer, anti-bacteria properties. The recent prevalence of the COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has aroused attention to investigate the antiviral potential of Au(I) compounds. Herein we demonstrate the pan-anti-SARS-CoV-2 activity of Au(I) metallodrugs in mammalian cells. We synthesized a panel of Au(I)-based compounds and found that these compounds could effectively inhibit the exoribonuclease and methyltransferase activities of SARS-CoV-2 nsp14/nsp10 complex, and the ATPase and DNA unwinding activities of SARS-CoV-2 nsp13 (helicase). Mechanistic studies reveal that Au(I) can not only displace the critical Zn(II) ions from nsp14/nsp10 complex and nsp13 but also changes the secondary and quaternary structure of nsp14 and perturbate the DNA unwinding of nsp13 by disrupting the ATP binding. This study illustrates a multi-target feature Au(I) compounds/drug agents for the viruses, highlighting their potential as pan-anti-SARS-CoV-2 (or relevant viruses) agents.