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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 plitidepsine 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 removed for use, could provide an additive effect when given in combination.
“The potency of the inhibitor is quite amazing,” said lead author Adolfo Garcia-Sastre, Ph.D. Medscape medical news.
Given prophylactically, plitidepsin also reduced the viral replication in the lungs of two different models of mice of two orders of magnitude.
Plitidepsin works by inhibiting the host eEF1A protein, not the virus, which could be an advantage because it avoids the problems associated with future viral resistance.
The study was published online on January 25 in 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 plitidepsine should be considered in extensive clinical trials for the treatment of COVID-19, the researchers note.
However, these are the first days. “We have found a strong inhibitor of SARS-CoV-2 replication, but clinical trials are still needed to see if it benefits patients,” added Garcia-Sastre, director of the Global Institute of Emerging Health for Pathogens at the School of Icahn Medicine at Mount Sinai in New York.
Because plitidepsine is an antiviral agent, it “inhibits the replication of the virus and should be administered during the active replication phase of COVID-19. Similar to remdesivir and all other antiviral medicines, the sooner you are given, the better the chance it has to be effective, “said lead author Kris M. White, PhD, assistant professor of microbiology, School of Medicine. Icahn from Mount Sinai. Medscape medical news.
A lack of therapy
Investigators point out that current therapies for patients with COVID-19 include oxygen therapy, ventilation, remdesivir, and steroid dexamethasone. They add that “remdesivir has shown particularly 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 therapy, they investigated the reuse of existing agents. This led them to investigate the antiviral potential of plitidepsin against SARS-CoV-2. Plitidepsin was originally discovered in the sea jet Ecology albicans.
In both human 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 in 24 hours. The agent significantly reduced genomic RNA content at 8 and 12 hours after infection in Vero e6 cells and decreased “at a significant time to 24 hours”, they note, similar to remdesivir.
“This laboratory study of plitidepsine showed that the drug achieves one of the targets in animal cells that the SARS-CoV-2 virus must reproduce. It reduces the replication of the virus in vitro, although up to 24 hours there was no statistically significant reduction. of the amount of viral RNA, “said Robin Ferner, MD Medscape medical news when asked to comment.
“It has 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 United Kingdom and associate professor at University College London.
Further validated findings in mice
Garcia-Sastre and colleagues showed a nearly 2-day reduction in SARS-CoV-2 viral titers in the lungs of plitidepsin-treated mice compared to others treated with a vehicle control.
“These experiments show that plitidepsine 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,” the researchers write.
Ferner issued a warning about potential side effects. “The drug was used experimentally to treat patients with multiple myeloma, but the side effects are common and included elevated liver enzymes,” in a 2019 study, he said.
On a more positive note, plitidepsin “removed the first obstacles 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 led to plitidepsin already having a established safety profile with concomitant dexamethasone treatment and should allow clinicians to treat both drugs, if warranted, the researchers note.
In the big 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 interesting candidate for further 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 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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