The science reported that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (IC90 = 0.88 nM) 27.5-fold more potent than remdesivir against SARS-CoV-2 in vitro, with limited toxicity in cell culture (1). Plitidepsin has successfully completed a phase I/II clinical study for the treatment of COVID-19 (20, 21) by the pharmaceutical company PharmaMar and is moving forward into a Phase II/III COVID-19 study.
Through the use of a drug resistant mutant, it was shown that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A. The in vivo efficacy of plitidepsin treatment was demonstrated 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. The antiviral effect of plitidepsin was tested in an established model of human pneumocyte-like cells. The treatment with plitidepsin inhibited SARS-CoV-2 replication with an IC90 of 3.14 nM and a selectivity index of 40.4, suggesting that plitidepsin has potent antiviral activity in primary human lung cells.
Plitidepsin is a marine cyclic depsipeptide in phase II clinical development against several neoplasias. It was shown earlier that plitidepsin is a potent inducer of apoptosis through the sustained activation of Jun N-terminal kinase (JNK) (2). Depletion of plasma membrane cholesterol of HeLa cells by short treatment with methyl-β-cyclodextrin diminished plitidepsin binding and Rac1 and JNK activation. Rac1 is targeted to the plasma membrane by plitidepsin as shown by subcellular fractioning and immunofluorescence analysis followed by confocal microscopy. Methyl-β-cyclodextrin blocked this effect. it was concluded that cellular plitidepsin uptake and induction of apoptosis via activation of the Rac1-JNK pathway is membrane-cholesterol dependent.
(1) White, KM et al. (2021) Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science eabf4058. https://science.sciencemag.org/content/early/2021/01/22/science.abf4058
(2) Suárez, Y., González-Santiago, L., Zarich, N., (…), Rojas, J.M., Muñoz, A. (2006) Plitidepsin cellular binding and Rac1/JNK pathway activation depend on membrane cholesterol content. Molecular Pharmacology 70(5), pp. 1654-1663. DOI: https://doi.org/10.1124/mol.106.025569