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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-fold 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 removed for use, may provide an additive effect when administered in combination.
“The potency of the inhibitor is quite amazing,” said the author, Dr. Adolfo Garcia-Sastre, Dr. Medscape Medical News.
Given prophylactically, plitidepsin also reduced viral replication in the lungs of two different mouse models in two orders of magnitude.
Plitidepsin works by inhibiting the host’s eEF1A protein, not the virus, which could be an advantage because it prevents problems associated with future viral resistance.
The study was published online on January 25 a Science.
Early Data, Early Administration
The preclinical efficacy shown in this study and in a phase 1/2 clinical trial by the manufacturer suggests “that plitidepsin should be strongly considered for extended clinical trials for the treatment of COVID-19,” the researchers note.
Still, these are the early days. “We have found a potent inhibitor of SARS-CoV-2 replication, but clinical trials are still needed to see if it provides a benefit to patients,” added Garcia-Sastre, director of the World Institute of Emerging Pathogens for the Health of the Faculty of Medicine Icahn. at Mount Sinai in New York City.
Because plitidepsin is an antiviral agent, it “inhibits the replication of the virus and should be given during the active replication phase of COVID-19. Similarly to remdesivir and other antiviral drugs, as soon as you are given more chances you’ll have has to be effective, ”said lead author Kris M. White, PhD, assistant professor of microbiology at Mount Sinai Icahn School of Medicine. Medscape Medical News.
A therapeutic poverty
The researchers note that current therapies for patients with COVID-19 include oxygen treatment, ventilation, remdesivir, and dexamethasone steroid. 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 continued need for development or reuse of antiviral drugs for the treatment of COVID-19,” they point out.
Faced with 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. Plitidepsin was initially discovered in sea splash Ecology of 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 content at 8 and 12 hours after infection in Vero e6 cells and fell “insignificantly at the 24-hour time point,” they note, similarly. when remdesivir.
“This laboratory study of plitidepsin showed that the drug hits one of the targets of the animal cells that the SARS-CoV-2 virus needs to replicate. It reduces the replication of the virus in vitro, although in 24 hours there is no there has been no statistically significant reduction in the amount of viral RNA, ”said Robin Ferner, MD 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 in the UK and associate professor at University College London.
Most validated results in mice
Garcia-Sastre and colleagues showed a reduction of nearly 2 records in SARS-CoV-2 viral titers in the lungs of plitidepsin-treated mice compared with others treated with a vehicle control.
“These experiments show that treatment with plitidepsin 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,” they write. the investigators.
Ferner raised a warning about possible adverse effects. “The drug has been used experimentally to treat patients with multiple myeloma, but adverse effects are common and include elevated liver enzymes,” in a 2019 study, he said.
On a more positive note, plitidepsin “has removed the first obstacles in the long race phase 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 led to plitidepsin already having an established safety profile with concomitant treatment with dexamethasone and should allow clinicians to treat with both drugs if justified,” the researchers note.
In general, inhibition of eEF1A may be a good pharmacological 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, although we expect our results to accelerate the execution of a phase 3 clinical trial,” Garcia-Sastre said.
Science. Published online January 25, 2021. Full text
Damian McNamara is a Miami-based journalist. It covers a wide range of medical specialties, including infectious diseases, gastroenterology and neurology. Follow Damian on Twitter: @MedReporter.
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