Hurting the virus by targeting the host Many host proteins play a role in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some are required for viral replication and translation. There are efforts toward finding drugs that target viral proteins, but a complementary approach is to target these required host proteins. White et al. explored the antiviral activity of the cyclic depsipeptide drug plitidepsin, which targets the hosts cell's translational machinery (see the Perspective by Wong and Damania). The authors show that in cells, the drug is substantially more potent than remdesivir against SARS-CoV-2, with limited cellular toxicity. Prophylactic treatment protected mice against SARS-CoV-2 infection, so further investigation of plitidepsin as a therapeutic is warranted. Science , this issue p. 926 ; see also p. 884