Plitidepsin (Aplidine) is a potent anti-cancer agent by targeting eEF1A2 (?KD=80?nM). Plitidepsin possesses antiviral activity and is against SARS-CoV-2 with an IC90 of 0.88 nM. Plitidepsin is usually used for multiple myeloma and advanced cancer research, and has the potential for COVID-19 research[2].In Vitro: Plitidepsin (20 nM; 1 h) induces a dose-dependent decrease in VEGF secretion in MOLT-4 cells.?Plitidepsin (20 nM; 1 h) does not result in significant inhibition of VEGF-R1 mRNA in normal endothelial cells, which do express VEGFR-1 but do not secrete VEGF.?Plitidepsin inhibits SARS-CoV-2 with an IC90?of 1.76 nM. In hACE2-293T cells, Plitidepsin exhibits anti–SARS-CoV-2 activity with an IC90 of 0.88 nM. In an established model of human pneumocyte-like cells, Plitidepsin inhibits SARS-CoV-2 replication with an IC90?of 3.14 nM and a selectivity index of 40.4.In Vivo: Plitidepsin (intraperitoneal?injection; 0.3 mg/kg or 1 mg/kg; 2 hours before infection with SARS-CoV-2) significantly reduces SARS-CoV-2 infection in BALB/c mice expressing human ACE2. 0.3 mg/kg plitidepsin group results in a reduction of nearly 2 log units in SARS-CoV-2 viral titers in the lungs, and the 1 mg/kg group leads to? a reduction of 1.5 log units relative to the vehicle control group[2].