Abstract
Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.
Highlights
The antiviral activity of plitidepsin was evaluated by three separate teams against different coronavirus species, strains and variants
46 hospitalized COVID-19 patients were enrolled across 10 sites in Spain (Fig 4)
One large collaborative effort systematically mapped the interactome between SARS-CoV-2 proteins and human proteins, identifying several dozens of potentially druggable interactions [11]
Summary
More than 1 yr after being officially declared a pandemic, substantial disease burden remains, as the clinical course from severe lung involvement, evolving to respiratory failure continues to be the main cause of death for COVID-19 patients. Within the lipid bilayer envelope, the viral single-stranded RNA genome is packaged within a protein capsid, which comprised the nucleocapsid (N) protein [6]. The SARS-CoV-2 N protein, as well as several proteins from other viruses, has been shown to bind directly to eukaryotic elongation factor 1α (eEF1A), an important host factor for the replication of many viral pathogens [7, 8]. Down-regulation via small interfering RNA or chemical inhibition of eEF1A has been shown to result in a significant reduction in the replication and infectivity of several viruses, including SARS-CoV-2 [9, 10, 11]
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