Abstract
The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100 structurally diverse metal complexes for profiling as inhibitors of two relevant SARS‐CoV‐2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain‐like protease PLpro. In addition to many well‐established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal‐based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PLpro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS‐CoV‐2 assays confirming activity for gold complexes with N‐heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal‐based SARS‐CoV‐2 antiviral agents.
Highlights
Started in late 2019, the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the year 2020 has caused an uncontrolled pandemic and an unprecedented global health crisis.[1]
More than 100 structurally diverse metal complexes were investigated against two relevant protein targets of coronaviruses, namely the S/angiotensin-converting enzyme receptor 2 (ACE2) interaction and the protease papain-like protease (PLpro)
The most pronounced activity against the S/ACE2 interaction was observed with polyoxometalates, some of which achieved IC50 values in the nanomolar concentration range
Summary
Started in late 2019, the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the year 2020 has caused an uncontrolled pandemic and an unprecedented global health crisis.[1]. The potential antiviral application of various gold complexes had been reported before in the literature.[7] Notably, for the lead compound of gold drugs, auranofin (Au-1), antiviral activity against SARS-CoV-2 has already been confirmed within early drug repurposing efforts for Covid-19 treatment.[16] Our recent report demonstrated that inhibition of PLpro and interference with the S protein are likely among the key mechanisms of the antiviral activity of auranofin (Au-1) and other gold complexes.[6] For the profiling, we selected an extended number of 36 structurally diverse gold complexes with gold in the oxidation states +1 or +3 and different types of co-ligands, including N-heterocyclic carbenes (NHCs), alkynyls, dithiocarbamates, phosphines and chlorides. In this work we analyze 11 rhodium complexes with NHC ligands representing a class of organometallic compounds, for which we had reported promising biological properties recently.[21]
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