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 Plitidepsin is a host-targeted antiviral against SARS-CoV-2, with potent efficacy both in vitro and in mouse models. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro by a factor of 27.5, with limited toxicity in cell culture. Through the use of a drug-resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A (eukaryotic translation elongation factor 1A). We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.
【초록키워드】 COVID-19, Treatment, severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, Efficacy, coronavirus, Antiviral, translation, SARS-COV-2 infection, Remdesivir, lung, Toxicity, antiviral effects, Viral proteins, drug, in vitro, antiviral activity, severe acute respiratory syndrome Coronavirus, virus, inhibitors, Viral, cells, mice, viral replication, Lungs, Cell culture, therapeutic, target, Plitidepsin, mutant, respiratory, Mouse models, in vivo, inhibitor, mouse model, cellular, host proteins, complementary, elongation factor, life cycle, Science, reduction, acute respiratory syndrome, Factor, Viral protein, depsipeptide, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, Perspective, host protein, white, effort, approval, inhibitory concentration, prophylactic treatment, aplidin, Host, approach, Cell, required, magnitude, translational, eukaryotic translation, drug-resistant, 【제목키워드】 SARS-CoV-2, Efficacy, host protein,