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Although the evidence is preclinical, a new study shows that the antiviral agent plitidepsin (Aplidine) can block the proliferation of the SARS-CoV-2 virus in different cell lines and in the lungs of mice.
The antiviral activity of plitidepsin was almost 28 times stronger than that of remdesivir against SARS-CoV-2 in in vitro research. The researchers also noted that the two agents act on different targets, so remdesivir and plitidepsin, if released for use, can provide an additive effect when administered in combination.
“The potency of the inhibitor is quite surprising,” said senior author Adolfo Garcia-Sastre, PhD. Medscape Medical News.
Prophylactically given, plitidepsin also reduced viral replication in the lungs of two different mouse models by two orders of magnitude.
Plitidepsin acts by inhibiting the protein eEF1A in the host, not the virus, which can be an advantage, as it avoids problems associated with future viral resistance.
The study was published online on January 25 in Science.
Initial data, initial administration
The preclinical efficacy shown in this study and in a manufacturer’s phase 1/2 clinical trial suggests “that plitidepsin should be strongly considered for expanded clinical studies for the treatment of COVID-19,” the researchers note.
Still, it is still early. “We found a potent inhibitor of SARS-CoV-2 replication, but clinical trials are still needed to find out if it benefits patients,” added Garcia-Sastre, director of the Global Health Emerging Pathogens Institute at the Icahn School of Medicine in Monte Sinai in New York.
Since plitidepsin is an antiviral agent, “it inhibits replication of the virus and needs to be administered during the active replication phase of COVID-19. Similar to remdesivir and all other antiviral drugs, the sooner it is administered to you, the better chance has to be effective, “said lead author Kris M. White, PhD, assistant professor of microbiology at the Icahn School of Medicine on Mount Sinai. Medscape Medical News.
A Paucity of Therapeutics
The researchers note that current therapies for patients with COVID-19 include treatment with oxygen, ventilation, remdesivir and the steroid dexamethasone. They add that “remdesivir in particular has shown limited effectiveness and dexamethasone is a steroid that does not directly inhibit viral replication.
“This leaves an ongoing need to develop or reuse antiviral drugs for the treatment of COVID-19,” they note.
Given the need for effective therapy, they investigated the reuse of existing agents. This led them to investigate the antiviral potential of plitidepsin against SARS-CoV-2. Plithidepsin was first discovered in seawater Aplidium albicans.
In both human cells and Vero e6 cells, or kidney cells derived from African green monkeys, the researchers demonstrated a cytostatic effect of plitidepsin. They added the antiviral at different times over the course of 24 hours. The agent significantly reduced the content of genomic RNA 8 and 12 hours after infection in Vero e6 cells and dropped “insignificantly at the 24-hour time point”, they note, similar to remdesivir.
“This laboratory study of plitidepsin showed that the drug targets one of the targets in animal cells that the SARS-CoV-2 virus needs to replicate. It cuts off replication of the virus in vitro, although within 24 hours there was no statistically significant reduction in the amount of viral RNA, “Robin Ferner, MD, said Medscape Medical News when asked to comment.
“It also reduced infection in mice if administered before the virus,” said Ferner, whose honorary positions include professor of clinical pharmacology at the University of Birmingham, UK, and associate professor at University College London.
Findings validated later in mice
Garcia-Sastre and colleagues showed an almost 2-log reduction in SARS-CoV-2 viral titers in the lungs of mice treated with plitidepsin compared to others treated with a control vehicle.
“These experiments show that treatment with plitidepsin can reduce the replication of SARS-CoV-2 by 2 orders of magnitude and reduce lung inflammation in vivo and has significant potential for clinical efficacy for the treatment of COVID-19,” wrote the researchers. .
Ferner made a reservation about the potential adverse effects. “The drug was used experimentally to treat patients with multiple myeloma, but adverse effects are common and included increased liver enzymes” in a 2019 study, he said.
On a more positive note, plithidepsin “overcame the first hurdles in the long obstacle course to show clinical effectiveness in COVID-19. Most runners crash long before the end of the race,” said Ferner.
Future Implications
Interestingly, dexamethasone is also commonly used to treat people with multiple myeloma. “This meant that plitidepsin already had an established safety profile with the concomitant treatment of dexamethasone and should allow doctors to treat both drugs, if necessary,” the researchers note.
Overall, eEF1A inhibition may be a good drug target for other human coronaviruses and unrelated viral pathogens. “This potential for broad-spectrum antiviral activity makes plitidepsin an intriguing candidate for future exploration as a treatment for viral infections without clinically approved therapy,” the researchers note.
“We would like to study antiviral activity against other viruses in vitro and in animal models, while we hope that our results will accelerate the execution of a phase 3 clinical trial,” said Garcia-Sastre.
Science. Published online January 25, 2021. Full text
Damian McNamara is a team journalist who lives in Miami. It covers a wide range of medical specialties, including infectious diseases, gastroenterology and neurology. Follow Damian on Twitter: @MedReporter.
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