Metallodrug Profiling against SARS‐CoV‐2 Target Proteins Identifies Highly Potent Inhibitors of the S/ACE2 interaction and the Papain‐like Protease PL^pro

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 PL pro . 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 PL pro 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.

Biological Activity of Gold Compounds against Viruses and Parasitosis: A Systematic Review

“…Gold(I) complexes with N-heterocyclic carbene (NHC) or gold(III)-dithiocarbamato complexes [40] Plasmonium falciparum and Leishmania infantum Gold(I) complexes combined with triclosan [41,42] Protozoa and Helminth infections Gold(I) complex [43] Leishmania major, Toxoplasma gondii and Trypanosoma Gold(I)-carbene complexes [44] [40]…”

“…Gold(I) complexes with N-heterocyclic carbene (NHC) or gold(III)-dithiocarbamato complexes [40] Plasmonium falciparum and Leishmania infantum Gold(I) complexes combined with triclosan [41,42] Protozoa and Helminth infections…”

“…The inhibition can occur by means of one of two replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain-like protease PLpro. The chloroauric acid (HAuCl 4 ; oxidation state + 3) has moderate inhibition (about 47% inhibitory activity, the other gold compounds were poorly active or inactive) [40].…”

“…were selected for the SARS-CoV-2 antiviral assays. Among these, the gold(I) NHC complex (a) showed very promising activity at low micromolar concentration, and two gold(III)-dithiocarbamato complexes (b) and (c), Figure 4,were strongly active at the highest applied nontoxic dosage [40]. Auranofin inhibits SARS-CoV-2 replication in human cells (Huh7 cells) at a low micromolar concentration (EC50 1.4 μM).…”

In Vitro Anti-SARS-CoV-2 Activity of Selected Metal Compounds and Potential Molecular Basis for Their Actions Based on Computational Study

“…We refer, for instance, to the studies carried out by various authors on bismuth, gold, and rhenium compounds [ 18 , 19 , 20 , 21 ]; moreover, various laboratories—including ours—proposed the clinically established antiarthritic drug Auranofin as an effective antiviral drug candidate through a repurposing strategy [ 22 , 23 ]. More recently, Ingo Ott and coworkers carried out a systematic screening on a large panel, including more than 100 inorganic compounds, for their ability to inhibit the S/ACE2 interaction and the Papain-like Protease PLpro [ 24 ]. In any case, no truly effective metal-based drug of straightforward clinical use for COVID-19 treatment has been identified so far.…”