Drug repositioning is the only feasible option to immediately address the COVID-19 global challenge. We screened a panel of 48 FDA-approved drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which were preselected by an assay of SARS-CoV. We identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low 50% inhibitory concentrations (IC ₅₀ s), and in particular, two FDA-approved drugs—niclosamide and ciclesonide—were notable in some respects.

Stephania tetrandra and other related species of Menispermaceae are the major sources of the bis-benzylisoquinoline alkaloids tetrandrine (TET), fangchinoline (FAN), and cepharanthine (CEP). Although the pharmacological properties of these compounds include anticancer and anti-inflammatory activities, the antiviral effects of these compounds against human coronavirus (HCoV) remain unclear. Hence, the aims of the current study were to assess the antiviral activities of TET, FAN, and CEP and to elucidate the underlying mechanisms in HCoV-OC43-infected MRC-5 human lung cells. These compounds significantly inhibited virus-induced cell death at the early stage of virus infection. TET, FAN, and CEP treatment dramatically suppressed the replication of HCoV-OC43 as well as inhibited viral S and N protein expression. The virus-induced host response was reduced by compound treatment as compared with the vehicle control. Taken together, these findings demonstrate that TET, FAN, and CEP are potential natural antiviral agents for the prevention and treatment of HCoV-OC43 infection.

Significance: Recent spread of SARS-CoV-2 has sparked significant health concerns of emerging infectious viruses. Drug repurposing is a tangible strategy for developing antiviral agents within a short period. In general, drug repurposing starts with virtual screening of approved drugs employing docking simulations. However, the actual hit rate is low, and most of the predicted compounds are false positives. To tackle the challenges, we report advanced virtual screening with pre- and postdocking pharmacophore filtering of 6,218 drugs for COVID-19. Notably, 7 out of 38 compounds showed efficacies in inhibiting SARS-CoV-2 in Vero cells. Three of these were also found to inhibit SARS-CoV-2 in human Calu-3 cells. Furthermore, three drug combinations showed strong synergistic effects in SARS-CoV-2 inhibition at their clinically achievable concentrations.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea that is characterized by severe hemorrhage and a high fatality rate. Currently, no specific vaccine or treatment has been approved for this disease. To develop a therapeutic agent for SFTS, we isolated antibodies from a phage-displayed antibody library that was constructed from a patient who recovered from SFTS virus (SFTSV) infection. One antibody, designated as Ab10, was reactive to the Gn envelope glycoprotein of SFTSV and protected host cells and A129 mice from infection in both in vitro and in vivo experiments. Notably, Ab10 protected 80% of mice, even when injected 5 days after inoculation with a lethal dose of SFTSV. Using cross-linker assisted mass spectrometry and alanine scanning, we located the non-linear epitope of Ab10 on the Gn glycoprotein domain II and an unstructured stem region, suggesting that Ab10 may inhibit a conformational alteration that is critical for cell membrane fusion between the virus and host cell. Ab10 reacted to recombinant Gn glycoprotein in Gangwon/Korea/2012, HB28, and SD4 strains. Additionally, based on its epitope, we predict that Ab10 binds the Gn glycoprotein in 247 of 272 SFTSV isolates previously reported. Together, these data suggest that Ab10 has potential to be developed into a therapeutic agent that could protect against more than 90% of reported SFTSV isolates. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea. The tick-borne virus that causes SFTS has infected more than 5,000 humans, with a 6.4% to 20.9% fatality rate. Currently, there are no prophylactic or therapeutic measures against this virus. Historically, antibodies from patients who recovered from viral infection have been used to treat new patients, and commercially available antiviral monoclonal antibodies have been developed. Palivizumab was approved for the prophylaxis of respiratory syncytial virus (RSV) infection, and ibalizumab-uiyk was recently approved for the treatment of human immunodeficiency virus (HIV)-infected patients. To develop an antiviral monoclonal antibody for SFTS patients, we selected 10 antibodies from a patient who recovered from SFTS and found that one antibody potently inhibited SFTS viral infection both in vitro and in animal studies. We mapped the binding site of this antibody on the SFTS virus, which allowed us to predict that this antibody could bind 247 out of the 272 SFTS virus isolates reported to date. We anticipate that this antibody could be developed into a therapeutic treatment against SFTS.

Drug repositioning represents an effective way to control the current COVID‐19 pandemic. Previously, we identified 24 FDA‐approved drugs which exhibited substantial antiviral effect against severe acute respiratory syndrome coronavirus 2 in Vero cells. Since antiviral efficacy could be altered in different cell lines, we developed an antiviral screening assay with human lung cells, which is more appropriate than Vero cell. The comparative analysis of antiviral activities revealed that nafamostat is the most potent drug in human lung cells (IC₅₀ = 0.0022 µM).

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to global public health. Herbal medicines and their derived natural products have drawn much attention in the treatment of COVID-19, but the detailed mechanisms by which natural products inhibit SARS-CoV-2 have not been elucidated. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection routes via lysosome- and transmembrane protease serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by the pharmacological inhibition or gene silencing of NPC1, which is mutated in patients with Niemann–Pick type C (NPC) displaying disrupted membrane cholesterol distribution. Finally, readily available local foods or herbal medicines containing PG root show similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that briefly disrupting the distribution of membrane cholesterol is a potential novel therapeutic strategy for SARS-CoV-2 infection.