Cu(I)-N-Heterocyclic carbenes as potent inhibitors of SARS-CoV-2 replication

SARS-CoV-2 still poses as a threat to health systems despite the vaccination and the use of emergency repurposed drugs. Therefore, the development of novel anti-SARS-CoV-2 compounds is still needed. Organometallic copper(I)-N-heterocyclic carbenes [Cu(NHC)] are a class of metallodrugs that hold promise for drug development due to their variety of geometries, charges, and ligand design. Here we evaluated the activity of Cu(IPr)Cl, Cu(IMes)Cl, and [Cu(IMes)₂]BF₄ molecules against SARS-CoV-2 infection. Through a dose–response assay using A549-AT cells and the SARS-CoV-2-Wuhan infectious clone expressing mNeonGreen (SARS-CoV-2-mNeonGreen), Cu(IPr)Cl, Cu(IMes)Cl, and [Cu(IMes)₂]BF₄ inhibited SARS-CoV-2 replication with a selectivity index (SI) of 11.23, 10.84, and 5.94, respectively. The complexes Cu(IMes)Cl and [Cu(IMes)₂]BF₄ inhibited all stages of viral replication (pretreatment: 99.9% and 87.7%, entry: 99.6% and 74%, post-entry steps: 99.6% and 87.6%, respectively), while Cu(IPr)Cl impaired only entry (48%) and post-entry steps (95%). In addition, Cu(IMes)Cl and [Cu(IMes)₂]BF₄ complexes decreased the titres of both Delta and Omicron variants, while Cu(IPr)Cl only inhibited Omicron. In addition, [Cu(IMes)₂]BF₄ was able to decrease cell to cell spread of SARS-CoV-2; and for Cu(IMes)Cl a strong interaction with PLpro was revealed. Based on this data further investigations of Cu(I) based organometallics are warranted and Cu(IPr)Cl and Cu(IMes)Cl may be considered for utilization in pre-clinical assays.