Chemical Identity

Property	Value
Chemical Formula	C46H63N5O10S
Molecular Weight	882.1 Da
CAS Number	137219-37-5
Peptide Class	Depsipeptide
Origin	Aplidium albicans (tunicate)

Structure

Plitidepsin is a cyclic depsipeptide originally isolated from the Mediterranean tunicate Aplidium albicans, now produced by total synthesis. It contains a threonine-derived oxazoline ring, a dehydrothreonine, and a unique (R)-lactyl-L-threonine residue. The molecule has a 19-membered macrolactone ring.

Mechanism of Action

Plitidepsin binds to eukaryotic elongation factor 1A2 (eEF1A), a GTPase essential for protein translation. This interaction inhibits protein synthesis and activates the oxidative stress pathway, JNK phosphorylation, and apoptosis. It also has demonstrated antiviral activity against SARS-CoV-2 by inhibiting viral protein translation.

Clinical Applications

• Multiple myeloma: Relapsed/refractory (Aplidin, approved in Australia)
• COVID-19: Investigational antiviral (reduces viral replication)
• Solid tumors: Under investigation in various tumor types
• T-cell lymphoma: Early clinical trials

Pharmacokinetics

• Half-life: 8-12 hours
• Protein binding: >95%
• Metabolism: Hepatic (CYP3A4)
• Distribution: Extensive tissue binding
• Route: IV infusion (1-hour)

Safety and Side Effects

Asthenia, nausea, myalgia, hepatotoxicity (transaminase elevation), thrombocytopenia, and CPK elevation. Premedication with corticosteroids reduces myalgia risk.

References

• Mateos, M.V., et al. (2020). Plitidepsin for multiple myeloma (ADMYRE). Leukemia, 34, 1193-1203.
• White, K.M., et al. (2021). Plitidepsin has potent preclinical efficacy against SARS-CoV-2. Science, 371, 926-931.