Silver N-heterocyclic carbene complexes are potent uncompetitive inhibitors of the papain-like protease with antiviral activity against SARS-CoV-2

The ongoing SARS-CoV-2 pandemic has caused a high demand for novel innovative antiviral drug candidates. Despite promising results, metal complexes have been relatively unexplored as antiviral agents in general and in particular against SARS-CoV-2. Here we report on silver NHC complexes with chloride or iodide counter ligands that are potent inhibitors of the SARS-CoV-2 papain-like protease (PL(pro)) but inactive against 3C-like protease (3CL(pro)) as another SARS-CoV-2 protease. Mechanistic studies on a selected complex confirmed zinc removal from a zinc binding domain of PL(pro) as relevant factor of their activity. In addition, enzyme kinetic experiments revealed that the complex is an uncompetitive inhibitor and with this rare type of inhibition it offers great pharmacological advantages in terms selectivity. The silver NHC complexes with iodide ligands showed very low or absent host cell toxicity and triggered strong effects on viral replication in cells infected with SARS-CoV-2, making them promising future antiviral drug candidates.