Virus World

Plitidepsin is a marine-derived cyclic-peptide that inhibits SARS-CoV-2 replication at low nanomolar concentrations by the targeting of host protein eEF1A (eukaryotic translation-elongation-factor-1A). We evaluated a model of intervention with plitidepsin in hospitalized COVID-19 adult patients where three doses were assessed (1.5, 2 and 2.5 mg/day for 3 days, as a 90-minute intravenous infusion) in 45 patients (15 per dose-cohort). Treatment was well tolerated, with only two Grade 3 treatment-related adverse events observed (hypersensitivity and diarrhea). The discharge rates by Days 8 and 15 were 56.8% and 81.8%, respectively, with data sustaining dose-effect. A mean 4.2 log10 viral load reduction was attained by Day 15. Improvement in inflammation markers was also noted in a seemingly dose-dependent manner. These results suggest that plitidepsin impacts the outcome of patients with COVID-19.

One-Sentence Summary Plitidepsin, an inhibitor of SARS-Cov-2 in vitro, is safe and positively influences the outcome of patients hospitalized with COVID-19.

Preprint available in medRxiv (May 25, 2021):

https://doi.org/10.1101/2021.05.25.21257505 

In two preclinical models of COVID-19, plitidepsin showed a 100-fold reduction in viral replication in the lungs and demonstrated an ability to reduce lung inflammation. Scientists at UC San Francisco’s Quantitative Bioscience Institute (QBI) and the Icahn School of Medicine at Mt. Sinai (ISMMS) in New York have shown that plitidepsin (Aplidin), a drug approved by the Australian Regulatory Agency for the treatment of multiple myeloma, has potent antiviral activity against SARS-CoV-2, the virus that causes COVID-19. In laboratory experiments reported in Science on Jan. 25, plitidepsin, a compound originally discovered in a Mediterranean sea squirt, was 27.5-fold more potent against SARS-CoV-2 than remdesivir, a drug that received FDA emergency use authorization in 2020 for the treatment of COVID-19. In addition, in two preclinical models of COVID-19, plitidepsin showed a 100-fold reduction in viral replication in the lungs and demonstrated an ability to reduce lung inflammation.  The studies were led by the laboratories of Nevan Krogan, PhD, director of the QBI, part of the UCSF School of Pharmacy, and Adolfo García-Sastre, PhD, professor of microbiology and director of the Global Health and Emerging Pathogens Institute at ISMMS.

In 2020, in response to the COVID-19 pandemic, Krogan, also a senior investigator at Gladstone Institutes, brought many UCSF labs together in the QBI Coronavirus Research Consortium (QCRG), which played a major role in the new research. In a separate publication posted to the bioRxiv preprint server, the UCSF and ISMMS researchers, in collaboration with Greg Towers, PhD, and Clare Jolly, PhD, of University College London, show that plitidepsin has antiviral activity against the recently identified B.1.1.7 variant of SARS-CoV-2 which is comparable to the drug’s activity against the original SARS-CoV-2 strain. Additionally, they found plitidepsin to be about 100 times more potent than remdesivir in human epithelial cells.    “From the start, our scientific investigations with the QCRG were to research where and how the SARS-CoV-2 virus was co-opting its human host to thrive, survive and become deadly,” said Krogan. “That research led us to a biologic pathway, the eukaryotic translation machinery, where inhibition of the pathway showed significant antiviral activity in cell culture. One of the promising agents that arose from our screen of drugs that inhibit this pathway was plitidepsin. Our preclinical data showing increased potency compared to remdesivir, and in conjunction with recent early clinical data showing promise in COVID-19 patients, as reported by the drug’s manufacturer, suggest plitidepsin should be further evaluated as a COVID-19 therapy.” García-Sastre said, “The ongoing COVID-19 pandemic has created an immediate need for antiviral therapeutics that can be moved into the clinic urgently. This led us to screen clinically approved drugs with established safety profiles. Our previous study of the SARS-CoV-2’s interactions with human host cells led us to  a protein  known as eEF1A, which is involved in translating mRNA into proteins, as a potential druggable target to inhibit SARS-CoV-2 replication.” 

The studies were conducted in close collaboration with PharmaMar, a Spanish pharmaceutical  company that first isolated plitidepsin (trade name Aplidin) from a sea organism known as Aplidium albicans. “Plitidepsin is an extremely potent inhibitor of SARS-CoV-2, but its most important strength is that it targets a host protein rather than a viral protein,” said Kris White, PhD, assistant professor of microbiology at ISMMS, first author of the Science paper. “This means that if plitidepsin is successful in the treatment of COVID-19, the SARS-CoV-2 virus will be unable to gain resistance against it through mutation, which is a major concern with the spread of the new U.K. and South African variants.” Krogan said the work is further validation of the QCRG’s focus on host proteins as a strategy to fight COVID-19 and other viral diseases. “It is host mechanisms that permit the SART-CoV-2 virus to wreak havoc,” Krogan said. “By targeting host factors that enable or facilitate disease, we have the potential to have a more far-reaching impact in drug development. In this case, SARS-CoV-2 and its mutant strains, and possibly other viruses that leverage the same pathway, may also be susceptible to the same therapeutic agents that inhibit this virus–host interaction.”

Cited Publications in Science (Jan. 25, 2021):

https://science.sciencemag.org/content/early/2021/01/22/science.abf4058 

bioRxix (Jan. 24, 2021):

https://doi.org/10.1101/2021.01.24.427991

The last time the world needed an antiviral medicine as quickly as possible, Daria Hazuda, vice president of infectious disease and vaccine discovery research at Merck, answered the call. Around 150,000 Americans were infected with HIV each year when rates peaked in the mid-1980s, and by the year 2000 nearly 500,000 people had died of AIDS in the U.S. Hazuda’s research at the time focused on HIV’s ability to insert its genetic material into the the human genome. Her lab developed a novel way to target that process with a drug called raltegravir, which was approved for use in 2007 and is still used today.  Now, she hopes to develop a drug for COVID-19 — at a substantially faster pace.  While most of the world’s attention is currently laser focused on getting vaccines to more people to stem the spread of the coronavirus, there’s also significant pressure on scientists to find a cure.  Doctors have some medications they can use to treat the effects of COVID-19, but developing a drug that targets the virus itself is a complex and costly procedure. More than a year into the pandemic only one antiviral treatment — remdesivir — is currently recommended for use in the U.S., and experts say it is not nearly effective enough. “Vaccine manufacturers are making next generation vaccines to try and stay one step ahead, but it is unpredictable. So you need other interventions to address the potential evolution of the virus,” Hazuda said. She and her team, along with researchers at Miami-based Ridgeback Biotherapeutics, worked seven days a week in the spring of 2020 to find a possible treatment for COVID-19 and prepare for the clinical trials necessary to prove its safety and effectiveness. Their drug, molnupiravir, is one of two powerful medicines to treat COVID-19 that are nearing the end of clinical testing.  “The day started really early and ended really late at night,” Hazuda said. “But there was a tremendous sense of mission. Everybody wanted to help even though they were exhausted. There was so much we all had to do.” Scientists are hopeful that new drugs designed to stop the virus’ deadly reproduction could reduce hospitalizations and deaths from COVID-19. The drugs offer hope and a contingency plan for unvaccinated individuals, particularly in low-income countries lagging far behind in the race to vaccinate. 

Chasing a moving target

Viruses mutate constantly, making it challenging to find a medicine that will not just work, but continue to work as the virus morphs. Mutations can change the shape of viruses’ proteins and thereby make them resistant to drugs. The hunt for effective antivirals is largely a hunt for a “conserved target,” such as a protein that rarely changes its shape even as the virus mutates.  Since scientists shared the sequenced genome of the novel coronavirus in January 2020 — detailing the specific genetic information and proteins of the virus — researchers have worked at breakneck speed to find a targeted medicine. Hazuda’s experience with HIV and Hepatitis C helped her team quickly rule out targets in the SARS-CoV-2 structure that were likely to change as the virus mutated and focus instead on “very highly conserved targets to minimize the potential of developing resistance,” she said.  Antiviral medications often target a virus during the process of replication, when it uses our cells’ resources to make copies of itself — leading to cell damage and the release of more virus. By early March of last year, Hazuda had narrowed her search to compounds aimed at proteins that could copy the virus’s genetic material. Her team came across a pre-clinical publication from an Emory University scientist on molnupiravir, a compound initially developed for influenza and other viruses. Research suggested the compound could make it harder for the virus to replicate itself by interrupting the RNA polymerase enzyme, which acts like a copy machine for the viral genome. In various academic labs, molnupiravir has demonstrated activity against flu and many different types of coronavirus, including MERS and the common cold.  “We were very interested in finding an agent that would have the potential to be not only active against CoV-2, but potential future outbreaks or pandemics caused by other coronaviruses,” Hazuda said. Because Ridgeback Biotherapeutics had the rights to molnupiravir, Merck began collaborating with the smaller pharmaceutical company to test the safety of the compound and prepare it for clinical studies.  The idea is that molnupiravir could be taken as an oral pill by symptomatic patients who test positive for COVID-19, before their illness is severe enough to require going to a hospital. The hope is that it can stop the virus in its tracks, before it can replicate uncontrollably and cause a person to become more sick. One phase 2 clinical study showed that molnupiravir is unlikely to significantly change the illness of those people who are hospitalized with COVID-19, but Hazuda is hopeful that phase 3 trials — expected to conclude by the end of the year — will demonstrate its effectiveness as a treatment that can be used outside of the hospital for people with mild to moderate cases.

Adolfo Garcia-Sastre, the director of the Global Health and Emerging Pathogens Institute at Icahn School of Medicine at Mount Sinai, also spent the spring of 2020 looking for a medication that could thwart the coronavirus’ lifecycle, but at a different stage. He sought a drug that influences the human proteins that the virus uses to build its components.  Because viruses hijack human cells and use their proteins (called factors) and other materials for their own purpose, identifying the factors they rely on can be a first step toward halting their actions.  Garcia-Sastre’s collaborators at the Quantitative Biosciences Institute at the University of California, San Francisco, identified more than 300 human factors most likely to make an impact on viral replication. Then, his lab tested around 90 drugs that are known to affect these factors. They landed on plitidepsin, an injectable medicine developed by Spain’s PharmaMar and used in patients with multiple myeloma, a type of blood cancer. It was shown to interfere with the function of a human factor called eEF1A, which the virus uses in the assembly of  its proteins. So far, plitidepsin seems to overcome some of the difficulties in finding a drug that targets virus replication. One is that often their effectiveness in the lab or in animal testing doesn’t carry over to humans. Another is toxicity: The concentrations required can cause undesired effects in human cells. Plitidepsin passed the critical phase 1 clinical trial conducted in Spain, showing that toxicity is not a barrier to use. The ongoing phase 3 clinical trial will show whether plitidepsin decreased days of hospitalization for COVID-19 patients.  The study, expected to be completed in August, will compare plitidepsin’s effectiveness to remdesivir, the current standard of care, which also works by inhibiting replication and can shorten hospitalization for COVID-19 patients by four days, on average. Where remdesivir has fallen short on decreasing the deadliness of the virus, Garcia-Sastre hopes plitidepsin will demonstrate live-saving potential.

The cost of discovery

While doctors have blood thinners and steroids to treat the symptoms of a raging COVID-19 illness, developing a new medicine that specifically targets the virus itself can take many years, explained Bhaven Sampat, an economist and associate professor at the Department of Health Policy and Management at the Mailman School of Public Health at Columbia University.  By repurposing an existing medicine and using already-developed compounds, both Garcia-Sastre and Hazuda shaved precious time off the drug development process. Piggybacking off already identified candidates also helps sidestep some of the cost spent on basic research. “That’s particularly useful because you don’t have to reinvent the wheel in a way,” Sampat said. Remdesivir, so far the only antiviral approved for COVID-19, benefited from the same leg up. Developed nearly a decade ago and shown effective against other coronaviruses including Ebola, SARS and MERS, it was fast tracked for use against COVID-19 and greenlit by the FDA in October 2020.  Another existing drug, ivermectin, may also have potential against SARS-CoV-2. A May meta-analysis suggests it could speed recovery and reduce mortality from COVID-19. The idea is controversial; some experts are unconvinced while proponents are eager to put it to use as a cheap, effective treatment. The anti-parasitic, developed by Merck in the 1980s, is no longer under patent. The company has contended there is not sufficient evidence for its use against COVID. Merck declined to respond to PBS NewHour’s request for comment. Developing a new drug oftentimes costs more than $1 billion dollars, a financial and technological burden typically shared by federally and grant-supported research labs (often at universities), which do basic research to identify drug candidates, and pharmaceutical companies, which bring medicines through expensive clinical trials to market.....