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Review
. 2021 Jul 16;11(7):668.
doi: 10.3390/jpm11070668.

Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19

Michail Papapanou  1   2 , Eleni Papoutsi  1 , Timoleon Giannakas  1 , Paraskevi Katsaounou  1   3
Affiliations
Review

Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19

Michail Papapanou et al. J Pers Med. .

Abstract

Current standard treatment of COVID-19 lacks in effective antiviral options. Plitidepsin, a cyclic depsipeptide authorized in Australia for patients with refractory multiple myeloma, has recently emerged as a candidate anti-SARS-CoV-2 agent. The aim of this review was to summarize current knowledge on plitidepsin's clinical profile, anti-tumour and anti-SARS-CoV-2 mechanisms and correlate this with available or anticipated, preclinical or clinical evidence on the drug's potential for COVID-19 treatment.PubMed, Scopus, CENTRAL, clinicaltrials.gov, medRxiv and bioRxiv databases were searched.Plitidepsinexerts its anti-tumour and antiviral properties primarily through acting on isoforms of the host cell's eukaryotic-translation-elongation-factor-1-alpha (eEF1A). Through inhibiting eEF1A and therefore translation of necessary viral proteins, it behaves as a "host-directed" anti-SARS-CoV-2 agent. In respect to its potent anti-SARS-CoV-2 properties, the drug has demonstrated superior ex vivo efficacy compared to other host-directed agents and remdesivir, and it might retain its antiviral effect against the more transmittable B.1.1.7 variant. Its well-studied safety profile, also in combination with dexamethasone, may accelerate its repurposing chances for COVID-19 treatment. Preliminary findings in hospitalized COVID-19 patients, have suggested potential safety and efficacy of plitidepsin, in terms of viral load reduction and clinical resolution. However, the still incomplete understanding of its exact integration into host cell-SARS-CoV-2 interactions, its intravenous administration exclusively purposing it for hospital settings the and precocity of clinical data are currently considered its chief deficits. A phase III trial is being planned to compare the plitidepsin-dexamethasone regimen to the current standard of care only in moderately affected hospitalized patients. Despite plitidepsin's preclinical efficacy, current clinical evidence is inadequate for its registration in COVID-19 patients.Therefore, multicentre trials on the drug's efficacy, potentially also studying populations of emerging SARS-CoV-2 lineages, are warranted.

Keywords: COVID-19; SARS-CoV-2; antiviral agents; aplidin; plitidepsin.

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Conflict of interest statement

M.P. reports a grant from the World Health Organization outside the submitted work. P.K. reports grants and personal fees outside the submitted work. E.P. and T.G. have nothing to disclose.

Figures

Figure 1
Figure 1
Plitidepsin’s host-directed anti-SARS-CoV-2 action mechanisms.SARS-CoV-2 possesses a single-stranded RNA (ssRNA) genome. The angiotensin converting enzyme-2 (ACE2) receptor is identified as the cell-surface receptor of SARS-CoV-2. Specific spike protein interactions with ACE2 receptors promote viral fusion with the cellular membrane. After entry, uncoating of the viral genomic RNA is followed by the translation of two large open reading frames (ORF), ORF1A and ORF1B. The resulting polyproteins, pp1a and pp1ab, are proteolyzed into non-structural proteins (nsps) that form the viral replication and transcription complex. This complex includes, amongst others, RNA-processing and RNA-modifying enzymes, such as RNA-dependent-RNA-polymerase, and drives the production of negative-sense RNAs ((−) RNAs). In general, the positive-sense genome can act as messenger RNA (mRNA) and can be directly translated into viral proteins, whereas negative-sense RNA is converted (via RNA-dependent-RNA-polymerase) into positive-sense RNA in order to be translated. Genomic RNA contains the necessary RNA regions required for genome replication and translation. During replication, full-length (−) RNA copies of the genome (genomic (−) RNAs) are used as templates for genomic (+) RNAs. During transcription, various subgenomic RNAs are produced through discontinuous transcription, where subgenomic (−) RNAs are synthesized by combining varying lengths of the 3′ end of the genome with the 5′ leader sequence necessary for translation. Subgenomic (−) RNAs are then transcribed into subgenomic (+) mRNAs. Resulting structural and accessory viral proteins are combined with genomic (+) RNAs to produce new viral particles, which will be secreted from the infected pneumonocyte by exocytosis. Through targeting the host cell’s eukaryotic translation elongation factor (eEF1A), plitidepsin inhibits the host-mediated translation of ORF1A, ORF1B and subgenomic mRNAs, leading to decreased production of viral pp1a and pp1ab andnsps, including RNA-dependent-RNA-polymerase, as well as structural and accessory proteins. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; ssRNA, single-stranded RNA; ACE2, angiotensin converting enzyme-2; ORF, open reading frame; mRNA, messenger ribonucleic acid; tRNA, transfer ribonucleic acid; eEF1A, eukaryotic translation elongation factor 1; GTP, guanosine triphosphate; pp, polyprotein.
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