Plitidepsin as an Immunomodulator against Respiratory Viral Infections

J Immunol. 2024 Apr 15;212(8):1307-1318. doi: 10.4049/jimmunol.2300426.


Plitidepsin is a host-targeted compound known for inducing a strong anti-SARS-CoV-2 activity, as well as for having the capacity of reducing lung inflammation. Because IL-6 is one of the main cytokines involved in acute respiratory distress syndrome, the effect of plitidepsin in IL-6 secretion in different in vitro and in vivo experimental models was studied. A strong plitidepsin-mediated reduction of IL-6 was found in human monocyte-derived macrophages exposed to nonproductive SARS-CoV-2. In resiquimod (a ligand of TLR7/8)-stimulated THP1 human monocytes, plitidepsin-mediated reductions of IL-6 mRNA and IL-6 levels were also noticed. Additionally, although resiquimod-induced binding to DNA of NF-κB family members was unaffected by plitidepsin, a decrease in the regulated transcription by NF-κB (a key transcription factor involved in the inflammatory cascade) was observed. Furthermore, the phosphorylation of p65 that is required for full transcriptional NF-κB activity was significantly reduced by plitidepsin. Moreover, decreases of IL-6 levels and other proinflammatory cytokines were also seen in either SARS-CoV-2 or H1N1 influenza virus-infected mice, which were treated at low enough plitidepsin doses to not induce antiviral effects. In summary, plitidepsin is a promising therapeutic agent for the treatment of viral infections, not only because of its host-targeted antiviral effect, but also for its immunomodulatory effect, both of which were evidenced in vitro and in vivo by the decrease of proinflammatory cytokines.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Cytokines / metabolism
  • Depsipeptides*
  • Humans
  • Immunologic Factors / pharmacology
  • Influenza A Virus, H1N1 Subtype*
  • Interleukin-6 / pharmacology
  • Mice
  • NF-kappa B* / metabolism
  • SARS-CoV-2 / metabolism


  • NF-kappa B
  • plitidepsin
  • Interleukin-6
  • Antiviral Agents
  • Immunologic Factors
  • Cytokines
  • Depsipeptides