Plitidepsin was originally obtained from a kind of protozoans, called Aplidiumalbicans. Plitidepsin, also known as dehydrodidemnin B, is a member of the class of compounds known as didemnins. Didemnins are belong to the family of cyclic depsipeptides which have the special structure with a side-chain. Didemnins and its analogs have attracted wide interest for study. In particular, in the case of didemnin B, it was the first marine secondary metabolite to enter clinical trials as an anticancer agent. Plitidepsin is also a cyclic depsipeptide, which not only can be isolated from natural sources, but also obtained by synthesis.
Synthesis of Plitidepsin
Semi-synthetic study for dehydrodidemnin B (plitidepsin) has been reported. Dehydrodidemnin B can be synthesized from Didemnin A. Firstly, L-proline benzyl ester is acylated with pyruvic acid to obtain benzyl (R)-1-(2-oxopropanoyl)pyrrolidine-3-carboxylate. Subsequently, the benzyl ester group underwent hydrolysis to give pyruvyl proline. Finally, the target dehydrodidemnin B is prepared by coupling of didemnin A, from either natural or synthetic sources, with pyruvyl proline.
Applications of Plitidepsin
Antitumor
Plitidepsin is a first-in-class anticancer drug developed by PharmaMar, which was entered into phase I clinical trials in 1999 under the auspices of PharmaMar for treatment of both solid tumors and non-Hodgkin’s lymphoma. Plitidepsin can binds specifically to eukaryotic translation elongation factor 1A2 (eEF1A2) and targets the atypical action of this protein, leading to tumor cell death through apoptosis (programmed death). Therefore, plitidepsin exhibits antitumor activities and it shows promise in shrinking tumors in pancreatic, stomach, bladder, and prostate cancers.
Non-Immunosuppressive
Didemnin B, as the very close analogue of plitidepsin, was discontinued in the clinical trials, due to its cytotoxicity and significant immunosuppression. In contrast, the plitidepsin was lack myelosuppression, which was proven by during using a murine competitive repopulating model as the test system. Moreover, no hematological toxicity of plitidepsin was observed in clinical practice. The removal of two hydrogen atoms of didemnin B, that is, conversion of the lactyl side chain to a pyruvyl side chain, appears to significantly alter the toxicity profile.
Antiviral
Plitidepsin is a drug with limited approval for the treatment of multiple myeloma. In a new study of against SARS-CoV-2 by conducting studies in preclinical models, plitidepsin was reported to be more effective than remdesivir, which was received emergency use authorization from the FDA in 2020 for the treatment of COVID-19.
Traditional antiviral drugs, such as remdesivir, target binding viral enzymes that tend to mutate, resulting in resistance, whereas antiviral drugs that target cellular host proteins required for viral replication can prevent viral resistance from developing. Plitidepsin, known to be an inhibitor of a protein involved in host protein translation, has been used to successfully complete a Phase I/II clinical study for the treatment of COVID-19. By using drug-resistant mutants, the antiviral activity of plitidepsin was proven to be mediated by inhibition of the known target eEF1A, which as a druggable target for the inhibition of SARS-CoV-2 replication.