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

Abstract

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.

Medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors

“…Wang et al 123 reported the emetine ( 56 , Fig. 28 ) can significantly influence SARS-CoV-2 entry and replication, meanwhile reducing inflammatory factor level in vitro .…”

Investigational antiviral drugs for the treatment of COVID-19 patients

“…Emetine has anti-malaria and anti-inflammatory properties. Moreover, it has shown antiviral activity against various DNA and RNA viruses such as Zika virus and Ebola virus [14,27,50,108,123]. Previous in vitro studies have demonstrated the inhibitory activity of emetine against MERS-CoV and SARS-CoV [38,101].…”

Phytochemicals for the treatment of COVID-19

“…Emetine, which has displayed inhibitory effects on Zika virus and Ebola virus (Yang et al, 2018), has been reported to reduce SARS-CoV-2 replication in a number of in vitro studies (Choy et al, 2020;Wang et al, 2020b;Jan et al, 2021;Kumar et al, 2021). A small observational study has also shown that, while emetine did not accelerate viral clearance, emetine appeared to improve blood oxygen concentrations and breathing difficulties among symptomatic COVID-19 patients (Fan et al, 2021).…”