Can plitidepsin be used as an antiviral against RSV?

Human respiratory syncytial virus (HRSV) is a main cause of acute lower respiratory tract infections in infants, the elderly, and immunocompromised patients. Although vaccines have recently been approved for the elderly and for pregnant women, there is no curative treatment for HRSV. HRSV replicates in the cytoplasm of infected cells, and transcription and replication of the viral genome depend on the viral RNA polymerase complex, which recruits cellular factors for RNA synthesis. Among them, the eukaryotic translation elongation factor 1A (eEF1A) was previously shown to be critical for HRSV replication. eEF1A activity can be inhibited by plitidepsin (Aplidin), a cyclopeptide extracted from the ascidian Aplidium albicans, which was shown to be highly potent against SARS-CoV-2, with a 50% inhibitory concentration (IC IMPORTANCE: Respiratory syncytial virus (RSV) is the main cause of bronchiolitis in infants and the elderly. Although some recent advances have been made, in particular vaccines for pregnant women and the elderly, or a new and efficient monoclonal prophylactic antibody for newborns, there is no curative treatment for human respiratory syncytial virus (HRSV). Previous works suggested that a natural compound extracted from a marine organism, plitidepsin, was capable of inhibiting virus replication, in particular SARS-CoV-2. Because the target of plitidepsin has been identified as the cellular protein eukaryotic translation elongation factor 1A (eEF1A) that brings tRNA-aa to the ribosome, and because it was published that RSV needs eEF1A, we tested plitidepsin against RSV. During this work, by using a non-radioactive pulse-chase labeling of protein synthesis, we found that plitidepsin blocks cellular translation with no specificity for the virus. We also observed that eEF1A was degraded after plitidepsin treatment in the BHK21-derived BSRT7 cell line, and that this degradation was inhibited by a proteasome inhibitor. However, this was not observed with Human HEp-2 or simian Vero E6 cell lines. So, we think that our results are new and original and that this information should be useful for the community working either with plitidepsin or eEF1A, with viruses, or other topics. We think that, in contrast to what is suggested by previous studies, it is risky to use plitidepsin as an antiviral in humans.