Low dose of emetine as potential anti-SARS-CoV-2 virus therapy: preclinical in vitro inhibition and in vivo pharmacokinetic evidences.

The global pandemic of COVID-19 has attracted extensive drug searching interets for the new coronavirus SARS-CoV-2. Although currently several of clinically used "old" drugs have been repurposed to this new disease for the urgent clinical investigation, there is still great demand for more effective therapies for the anti-infections. Here we report the discovery that an "old" drug Emetine could potently inhibit SARS-CoV-2 virus replication and displayed virus entry blocking effect in Vero cells at low dose. In addition, Emetine could significantly reduce the lipopolysaccharide (LPS) induced interleukin-6 (IL-6) protein level and moderately reduce the tumor necrosis factor (TNF-α) protein level in the M1 polarized THP-1 macrophages. In vivo animal pharmacokinetics (PK) study revealed that Emetine was enriched in the lung tissue and had a long retention time (over 12 h). With 1 mg/kg single oral dose, the effective concentration of Emetine in lung was up to 1.8 µM (mice) and 1.6 µM (rats) at 12 h, which is over 200-fold higher than the EC50 of the drug. The potent in vitro antiviral replication efficacy and the high enrichment in target tissue, combining with the well documented safety profiles in human indicate that low dose of Emetine might be a potentially effective anti-SARS-CoV-2 infection therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s43556-020-00018-9.

Repurposing of Kinase Inhibitors for Treatment of COVID-19.

The outbreak of COVID-19, the pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an intense search for treatments by the scientific community. In the absence of a vaccine, the goal is to target the viral life cycle and alleviate the lung-damaging symptoms of infection, which can be life-threatening. There are numerous protein kinases associated with these processes that can be inhibited by FDA-approved drugs, the repurposing of which presents an alluring option as they have been thoroughly vetted for safety and are more readily available for treatment of patients and testing in clinical trials. Here, we characterize more than 30 approved kinase inhibitors in terms of their antiviral potential, due to their measured potency against key kinases required for viral entry, metabolism, or reproduction. We also highlight inhibitors with potential to reverse pulmonary insufficiency because of their anti-inflammatory activity, cytokine suppression, or antifibrotic activity. Certain agents are projected to be dual-purpose drugs in terms of antiviral activity and alleviation of disease symptoms, however drug combination is also an option for inhibitors with optimal pharmacokinetic properties that allow safe and efficacious co-administration with other drugs, such as antiviral agents, IL-6 blocking agents, or other kinase inhibitors.