Selected metallo-compounds exhibit potent activity against SARS-CoV-2 in vitro. Historically, metal compounds have been used as antimicrobial agents. However, their antiviral activities have not been explored extensively. Our earlier studies demonstrated that bismuth drugs and related compounds exhibit excellent antiviral activity against SARS-CoV 21. Building on these results, we selected six metal compounds-two bismuth(iii) citrate-based drugs (colloidal bismuth subcitrate (CBS) and RBC, two bismuth(iii) porphyrins (Bi(TPP) (TPP, tetraphenylporphyrinate) and Bi(TPyP) (TPyP, tetra(4-pyridyl)porphyrin)), one Au(i)-based drug (Auranofin), as well as its active derivative, chloro(triethylphosphine) gold(i) (Au(PEt 3)Cl)-to carry out a primary evaluation against SARS-CoV-2 in vitro (Extended Data Fig. 1). The 50% cytotoxicity concentrations (CC 50) of these compounds in monkey kidney Vero E6 cells were determined to be 3,254 ± 21 μM for CBS, 2,243 ± 43 μM for RBC, >400 μM for both Bi(TPP) and Bi(TPyP), 14.2 ± 1.3 μM for auranofin and 13.5 ± 1.8 μM for Au(PEt 3)Cl (Extended Data Fig. 2). The four bismuth(iii) compounds were prioritized for further evaluation of their CC 50 values in human colorectal Caco-2 cells because of their promisingly low cytotoxicity compared with the Au(i)-based drugs, resulting in similar CC 50 values ranging from 400 to 3,740 μM (Extended Data Fig. 2). To evaluate their antiviral potency, the half-maximal effective doses (EC 50) of the bismuth(iii) compounds were determined at low micromolar levels as 4.6 ± 0.4 µM for CBS, 2.3 ± 0.5 µM for RBC, 3.9 ± 1.2 µM for Bi(TPP) and 7.5 ± 0.9 µM for Bi(TPyP). Remarkably, addition of all four bismuth(iii) compounds at 1 h post infection (h.p.i.) reduced viral RNA loads in both Vero E6 and Caco-2 cells in a dose-dependent manner (Fig. 1). In non-toxic concentrations, CBS and RBC exhibited more potent anti-SARS-CoV-2 activity than Bi(TPP) and Bi(TPyP), as evidenced by the maximal ~2-log versus 1-log viral load reduction in the Vero E6 cell lysate (Fig. 1a-d), ~3-log versus ~2-log reduction in the Caco-2 cell lysate (Fig. 1e-h), ~4-log versus ~3-log reduction in the Vero E6 cell culture supernatant (Fig. 1i-l) and ~4-log versus ~3-log reduction in the Caco-2 cell culture supernatant (Fig. 1m-p). Importantly, bismuth(iii) drugs/compounds greatly inhibited SARS-CoV-2, as evidenced by the markedly decreased expression of viral nucleoprotein in the drug-treated cells when compared with the dimethyl sulfoxide (DMSO)-treated group (Fig. 2a-f). To investigate which steps of the SARS-CoV-2 replication cycle were interrupted by the selected drug compounds, we performed a time-of-drug-addition assay by treating virus-infected cells with each compound at different time points, followed by measurements of viral titre after 9 h.p.i., when the first round of progeny virions were detectable in the cell culture supernatant. (Fig. 2g,h). Intriguingly, addition of Bi(TPyP) during pre-treatment or co-incubation of cells significantly suppressed virus replication, whereas n...

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