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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 various cell lines and in the lungs of mice.
The antiviral activity of plitidepsin was almost 28-fold stronger than that of remdesivir against SARS-CoV-2 in the in vitro study. The researchers also note that the two agents work for different purposes, so remdesivir and plitidepsin, when released before use, may have an additive effect when given in combination.
“The potency of the inhibitor is pretty amazing,” said senior author Adolfo Garcia-Sastre, PhD. Medscape Medical News.
Given prophylactically, plitidepsin also decreased 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 as it avoids problems associated with future viral resistance.
The study was published online Jan. 25 Science.
Early records, early records
The preclinical efficacy demonstrated in this study and in a phase 1/2 clinical study from the manufacturer “suggests that plitidepsin should be strongly considered for comprehensive clinical trials for the treatment of COVID-19,” the researchers note.
Yet they are still early days. “We have found a potent inhibitor of SARS-CoV-2 replication, but clinical trials are still needed to determine if it is of benefit to patients,” added Garcia-Sastre, director of the Global Health Emerging Pathogens Institute. the Icahn School of Medicine. on Mount Sinai in New York City.
Since plitidepsin is an antiviral agent, “it inhibits the replication of the virus and must be administered during the active replication phase of COVID-19. As with remdesivir and all other antivirals, the sooner it is given to you, the greater the chance.it has to be effective, ” lead author Kris M. White, PhD, assistant professor of microbiology, Icahn School of Medicine, told Mount Sinai. Medscape Medical News.
A lack of therapeutics
The researchers point out that current therapies for patients on COVID-19 include oxygen treatment, ventilation, remdesivir and the steroid dexamethasone. They add that “in particular, remdesivir has shown limited efficacy and that dexamethasone is a steroid that does not directly inhibit viral replication.
As a result, there remains a need to develop or repurpose antivirals for the treatment of COVID-19, they note.
Given the need for effective therapies, they investigated the repurposing of existing resources. This prompted them to explore plitidepsin’s antiviral potential against SARS-CoV-2. Plitidepsin was initially discovered in the sea syringe Ecology 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 for 24 hours. The agent significantly reduced genomic RNA levels at 8 and 12 hours after infection in the Vero e6 cells and fell “just short of significance at the 24-hour time point,” 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 decreases virus replication in vitro, although there is no statistically significant reduction after 24 hours. the amount was of viral RNA, “told Robin Ferner, MD Medscape Medical News when asked for comment.
“It also reduced infection in mice when given before the virus,” said Ferner, whose honorary posts include professor of clinical pharmacology at the University of Birmingham in the United Kingdom and associate professor at University College London.
Findings further validated in mice
Garcia-Sastre and colleagues showed an almost 2 log reduction in viral titers of SARS-CoV-2 in the lungs of mice treated with plitidepsin compared to others treated with a vehicle control.
“These experiments demonstrate that plitidepsin treatment can reduce SARS-CoV-2 replication by 2 orders of magnitude and reduce pneumonia in vivo and has significant potential for clinical efficacy for the treatment of COVID-19,” the researchers write. .
Ferner made a reservation regarding possible adverse effects. “The drug has been used experimentally to treat patients with multiple myeloma, but side effects are common and include elevated liver enzymes,” in a 2019 study, he said.
On the positive side, plitidepsin “took the first hurdles in the long steeplechase to show clinical efficacy in COVID-19. Most runners fall 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 resulted in plitidepsin already having a proven safety profile when treated concomitantly with dexamethasone and should allow physicians to treat with both drugs if warranted,” 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 further research as a treatment for viral infections without clinically approved therapeutics,” note the researchers.
“We want 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 personnel journalist based in Miami. It covers a wide variety of medical specialties, including infectious diseases, gastroenterology and neurology. Follow Damian on Twitter: @MedReporter.
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