The COVID-19 pandemic has created the need for antiviral therapeutics that can be swiftly moved into the clinic. This has led many researchers to search for a candidate through drug repurposing, or screening clinically approved antivirals for efficacy against SARS-CoV-2. While traditional antivirals, like remdesivir, target viral enzymes that are often subject to mutation, and thus to the development of drug resistance, antivirals that target the cell host proteins required for viral replication could have benefits, such as avoiding the development of resistance.
Working in preclinical models, researchers report that plitidepsin, a drug with limited clinical approval for the treatment of multiple myeloma, is more potent against SARS-CoV-2 than remdesivir—an antiviral that received FDA emergency use authorization for the treatment of COVID-19 in 2020.
The work is published in Science in the article, “Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eFF1A.”
SARS-CoV-2 viral proteins interact with the eukaryotic translation machinery. This opens up a door to combating infection by using inhibitors of translation, which have been shown to have antiviral effects. The authors assert that their results suggest that plitidepsin should be further evaluated as a COVID-19 therapy because it targets a host protein rather than a viral protein. Therefore, if treatment proves successful in humans, SARS-CoV-2 won’t be easily able to gain resistance against the drug through mutation.
In earlier work investigating host proteins likely to play a role in the viral life cycle of SARS-CoV-2, including a study published in Science in October of last year, Kris White, PhD, assistant professor of microbiology at the Icahn School of Medicine at Mount Sinai, and colleagues, found that targeting the host translation machinery that is used in the replication of many viral pathogens could greatly inhibit SARS-CoV-2.
Based on this, they evaluated plitidepsin, a known inhibitor of a protein involved in host protein translation. Through the use of a drug-resistant mutant, the authors showed that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A. In addition to having limited clinical approval for treating multiple myeloma, it has also successfully completed a Phase I/II clinical study for the treatment of COVID-19.
Here, in human cell studies, plitidepsin demonstrated potent anti-SARS-CoV-2 activity—27.5-fold more so than remdesivir as tested in the same cell line. It also showed limited toxicity in cell culture. In a model of human lung cells, plitidepsin greatly reduced viral replication. After further experiments involving remdesivir and plitidepsin in vitro, the researchers suggest that plitidepsin has an additive effect with this approved drug and would be a potential candidate for a combined therapy.
The team of researchers demonstrated the in vivo efficacy of plitidepsin treatment 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 mice who received the drug prophylactically had reduced viral load and lung inflammation compared to control mice.
This study, the authors noted, “establishes plitidepsin as a host-targeted anti-SARS-CoV-2 agent with in vivo efficacy.” They continued: “We believe that our data and the initial positive results from PharmaMar’s clinical trial suggests that plitidepsin should be strongly considered for expanded clinical trials for the treatment of COVID-19.”