Editor’s note: Find the latest COVID-19 news and guidance in Medscape’s Coronavirus Resource Center.
A new study shows that the antiviral drug plitidepsin (Aplidin) can block the spread 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 inhibitors of SARS-CoV-2 in the in vitro study. The researchers also note that the two drugs work on different targets, so remdesivir plus plitidepsin, if approved for use, can produce an additive effect when given in combination.
“The strength of the inhibitor is incredible,” said PhD senior writer Adolfo Garcia-Sastre. Medscape Medical News.
Preventively given, plitidepsin also reduced virus replication in the lungs of two different two-order mouse models.
Plitidepsin works by inhibiting the eEF1A protein in the host, not the virus, which may be beneficial because it avoids problems related to future virus resistance.
The study was published online on January 25 Science.
Early data, early administration
The preclinical efficacy demonstrated in this study and in a phase 1/2 clinical trial of the manufacturer suggests that ‘plitidepsin should be strongly considered for extensive clinical trials for the treatment of COVID-19’, the researchers say.
Yet it is 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,” said Garcia-Sastre, director of the Global Health Emerging Pathogens Institute at the Icahn School of Medicine, added. on Mount Sinai in New York City.
Because plitidepsin is an antiviral drug, “it inhibits the replication of the virus and should be given during the active replication phase of COVID-19. it must be effective, “said lead author Kris M. White, PhD, assistant professor of microbiology, Icahn School of Medicine at Mount Sinai Medscape Medical News.
Lack of therapeutic agents
The investigators point out that current therapies for patients with COVID-19 include oxygen therapy, ventilation, inhibitor and the steroid dexamethasone. They add that ‘especially inhibitor’ has a limited efficacy and that dexamethasone is a steroid that does not directly inhibit virus replication.
“This leaves a continuing need for the development or reuse of antiviral drugs for the treatment of COVID-19,” they note.
Because of the need for effective therapeutic agents, they investigated the reuse of existing drugs. This led them to investigate the antiviral potential of plitidepsin versus SARS-CoV-2. Plitidepsin was initially discovered in the sea spray Aplidium albicans.
In both human cells and Vero e6 cells, or kidney cells derived from African green monkeys, the researchers showed a cytostatic effect of plitidepsin. They added the antiviral drug at different times over 24 hours. The drug significantly reduced the genomic RNA content 8 and 12 hours after infection in the Vero e6 cells and ‘just less than the 24-hour time point’, they noted, similar to brake desivir.
“This laboratory study of plitidepsin showed that the drug meets one of the targets in animal cells that must repeat the SARS-CoV-2 virus. It reduces virus replication in vitro, although there was 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 when given before the virus,” Ferner said. His honorary positions include Professor of Clinical Pharmacology at the University of Birmingham in the United Kingdom and Associate Professor at University College London.
Findings are further confirmed in mice
Garcia-Sastre and colleagues showed a reduction in viral titers of SARS-CoV-2 by almost 2 logs in the lungs of mice treated with plitidepsin compared to others treated with a vehicle control.
“These experiments show that treatment with plitidepsin can reduce 2-order replication of SARS-CoV-2 and reduce pneumonia in vivo and has significant potential for clinical efficacy for the treatment of COVID-19,” the researchers write.
Ferner raised a reservation about possible adverse consequences. “The drug has been used experimentally to treat patients with multiple myeloma, but adverse effects are common and have included elevated liver enzymes,” he said.
On a more positive note, plitidepsin “cleared the first hurdles in the long haul 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 allowing clinicians to treat with both drugs if necessary,” the researchers say.
In the bigger picture, 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 interesting candidate for further investigation as a treatment for viral infections without clinically approved therapeutic agents,” the researchers say.
“We would like to study the antiviral activity against other viruses in vitro and in animal models, while hoping that our results will accelerate the implementation of a phase 3 clinical trial,” Garcia-Sastre said.
Science. Published online on January 25, 2021. Full text
Damian McNamara is a staff journalist in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology and neurology. Follow Damian on Twitter: @MedReporter.
Follow Medscape on Facebook for more news, Twitter, Instagram and YouTube.