Working in preclinical models, researchers report that plitidepsin, a drug with limited clinical approval for the treatment of multiple myeloma, is more potent against SARS-CoV-2 than remdesivir, an antiviral that received FDA emergency use authorization for the treatment of COVID-19 in 2020. The results suggest plitidepsin should be further evaluated as a COVID-19 therapy, the authors say; because it targets a host protein rather than a viral protein, if treatment proves successful in humans, the SARS-CoV-2 virus won't be easily able to gain resistance against the drug through mutation. The ongoing SARS-CoV-2 pandemic has created the need for antiviral therapeutics that can be swiftly moved into the clinic. This has led researchers to screen clinically approved antivirals. While traditional antivirals, like remdesivir, target viral enzymes that are often subject to mutation, and thus to the development of drug resistance, antivirals that target the cell host proteins required for viral replication could avoid resistance. In earlier work investigating host proteins likely to play a role in the viral life cycle of SARS-CoV-2, including a study in Science in October 2020, Kris White and colleagues found that targeting the host translation machinery that is used in the replication of many viral pathogens could greatly inhibit SARS-CoV-2. Based on this they evaluated plitidepsin, a known inhibitor of a protein involved in host protein translation. In addition to having a limited clinical approval for treating multiple myeloma, it has also successfully completed a phase I/II clinical study for the treatment of COVID-19. Here, in studies in human cells, plitidepsin demonstrated potent anti-SARS-CoV-2 activity - 27.5-fold more so than remdesivir as tested in the same cell line. In a model of human lung cells, plitidepsin greatly reduced viral replication. After further experiments involving remdesivir and plitidepsin in vitro, the researchers suggest that plitidepsin has an additive effect with this approved drug and would be a potential candidate for a combined therapy. The researchers also tested the drug in mice later infected with SARS-CoV-2. Mice who received the drug prophylactically had reduced viral load and lung inflammation compared to control mice. "We believe that our data and the initial positive results from PharmaMar's clinical trial suggests that plitidepsin should be strongly considered for expanded clinical trials for the treatment of COVID-19," conclude the authors.