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Although the evidence is preclinical, a new study shows that the antiviral agent plitidepsin (Aplidin) 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 note that the two agents act on different targets, so remdesivir and plitidepsin, if licensed for use, could provide an additive effect when given in combination.
“The potency of the inhibitor is quite surprising,” said lead author Adolfo García-Sastre, PhD. Medscape Medical News.
Administered prophylactically, plitidepsin also reduced viral replication in the lungs of two different mouse models by two orders of magnitude.
Plitidepsin works by inhibiting the eEF1A protein in the host, not the virus, which could be an advantage because it avoids problems associated with future viral resistance.
The study was published online January 25 at Sciences.
Initial data, early administration
The preclinical efficacy shown in this study and in a manufacturer’s phase 1/2 clinical trial suggests that “plitidepsin should be seriously considered for expanded clinical trials for the treatment of COVID-19,” the researchers note.
Still, it’s the early days. “We have found a potent inhibitor of SARS-CoV-2 replication, but clinical trials are still needed to determine if it provides a benefit to patients,” added García-Sastre, director of the Institute of Emerging Pathogens for Global Health at the Faculty. of Medicine of Icahn. at Mount Sinai in New York City.
Since plitidepsin is an antiviral agent, it “inhibits virus replication and must be administered during the active replication phase of COVID-19. Like remdesivir and all other antiviral medications, the earlier it is administered, the greater your be effective, “said lead author Kris M. White, PhD, assistant professor of microbiology at the Icahn School of Medicine at Mount Sinai. Medscape Medical News.
A shortage of therapies
The researchers note that current therapies for COVID-19 patients include oxygen therapy, ventilation, remdesivir, and the steroid dexamethasone. They add that “remdesivir in particular has shown limited efficacy and dexamethasone is a steroid that does not directly inhibit viral replication.
“This leaves a continuing need for the development or reuse of antiviral drugs for the treatment of COVID-19,” they note.
Given the need for effective therapies, they investigated the reuse of existing agents. This led them to investigate the antiviral potential of plitidepsin against SARS-CoV-2. Plitidepsin was initially discovered in sea squirts Albicans ecology.
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 during 24 hours. The agent significantly reduced genomic RNA content at 8 and 12 hours after infection in Vero e6 cells and was “just below significance at 24 hours,” they note, similar to remdesivir.
“This laboratory study of plitidepsin showed that the drug hits one of the targets in animal cells that the SARS-CoV-2 virus needs to replicate. It cuts off virus replication in vitro, although at 24 hours there was no reduction. statistically significant in the amount of viral RNA, “said Robin Ferner, MD, Medscape Medical News when asked to comment.
“It also reduced infection in mice if given before the virus,” said Ferner, whose honorary positions include professor of clinical pharmacology at the University of Birmingham in the UK and associate professor at University College London.
Most Validated Findings in Mice
García-Sastre and colleagues showed a nearly 2 log reduction in SARS-CoV-2 viral titers in the lungs of mice treated with plitidepsin compared to others treated with a vehicle control.
“These experiments show that plitidepsin treatment can reduce SARS-CoV-2 replication by 2 orders of magnitude and reduce lung inflammation in vivo and has significant potential for clinical efficacy for the treatment of COVID-19,” write the researchers.
Ferner issued a warning about possible adverse effects. “The drug has been used experimentally to treat multiple myeloma patients, but adverse effects are common and include an increase in liver enzymes” in a 2019 study, he said.
On a more positive note, plitidepsin “has overcome the first hurdles in the long obstacle course to show clinical efficacy in COVID-19. Most runners crash long before the end of the race,” Ferner said.
Future implications
Interestingly, dexamethasone is also commonly used to treat people with multiple myeloma. “This has led to plitidepsin already having an established safety profile with concomitant dexamethasone treatment and should allow clinicians to treat with both drugs if warranted,” the researchers note.
In the bigger picture, inhibition of eEF1A could 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 further exploration as a treatment for viral infections without clinically approved therapeutics,” 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 speed up the execution of a phase 3 clinical trial,” said García-Sastre.
Sciences. Published online January 25, 2021. Full text
Damian McNamara is a Miami-based staff journalist. Covers a wide range of medical specialties, including infectious diseases, gastroenterology, and neurology. Follow Damian on Twitter: @MedReporter.
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