560. Repurposing Eravacycline for the Treatment of SARS-CoV-2 Infections

Abstract Background The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is seriously impacting health and economies all over the world. With more than 8 million diagnosed cases and close to 450.000 deaths worldwide by mid-June 2020, the need of safe and effective treatments is extremely urgent. Drug repurposing is a suitable approach to bring new treatments to the clinics in a very fast and cost-effective way. Methods We have applied an artificial intelligence screening technology based on molecular fields to find drugs that could inhibit the SARS-CoV-2 3-chymotrypsin-like cysteine protease (3CLpro) among a library of compounds with clinical experience, approved drugs and drugs in clinical development. The results were refined by covalent docking at the catalytic domain of the protein and thirty compounds were chosen for experimental validation on a protease assay with recombinant SARS-CoV-2 3CLpro. The compounds were also tested for their inhibition of SARS-CoV and MERS-CoV 3CLpro. Positive hits were further tested in a VeroE6 cell infection assay with pathogenic SARS-CoV-2 using nucleocapsid protein staining at 24h post infection as a readout. Results Eravacycline was identified at the top positions of the screening and its potent inhibitory activity was demonstrated in vitro against recombinant SARS-CoV-2, SARS-CoV and MERS-CoV 3CL proteases, with IC50 of 1.65, 10.04 and 16.36 µM respectively. In addition, eravacycline inhibited infection of VeroE6 cells by pathogenic strains of SARS-CoV-2, with an IC50 of 30.61 µM in the absence of drug induced cell toxicity. Conclusion Eravacycline is an FDA and EMA-approved antibiotic that was launched in the US in 2018. It is a safe drug that is known to accumulate in the lungs at concentrations that are compatible with its in vitro activity against SARS-CoV-2. This, together with its known antibacterial activity that could help prevent secondary infections in hospitalized COVID-19 patients, and the known anti-inflammatory actions of tetracyclines, warrant further research on the potential role of eravacycline for the treatment of patients with COVID-19 or infected with SARS-CoV-2 but with milder symptoms. Disclosures Núria Reig, PhD, SOM Biotech (Employee) Dong-Hae Shin, PhD full professor, SOM Biotech (Scientific Research Study Investigator)