Experimental decoy drug tricks coronavirus, then destroys it

The coronavirus has been a sneaky enemy, with new variants and sub-variants rapidly evolving to evade vaccines and treatments. Researchers at Boston’s Dana-Farber Cancer Institute are working on an experimental drug that takes one of the virus’s most dangerous traits – its talent for mutation – and turns it against itself.

When the coronavirus binds to a specific type of receptor on the surface of a cell, it drives its spike protein like a switchblade and triggers an infection.

The drug is designed to mimic this receptor, functioning like an assassin in an attractive disguise. When the coronavirus tries to bind to it rather than the real thing, it destroys the structure of the spike protein, permanently disabling the mechanism that would make that switchblade, according to a report published Wednesday in the journal Science Advances. .

This approach pushes the coronavirus into a corner: if it adopts a mutation that makes it less efficient at binding to the decoy drug, it will also bind less efficiently to the human cell.

The virus has found ways to circumvent antibody treatments by developing new versions of its spike protein. But to circumvent that decoy, it would have to seek out and bind to a completely different receptor — a highly unlikely possibility “that would involve super drastic changes” in the virus, said Gordon Freeman, an immunologist at Dana-Farber and Harvard Medical School and lead author of the study.

“We’re not trying to fight evolution,” added Dr. James Torchia, clinical researcher at Dana-Farber and Harvard Medical School and lead author of the paper. “We’re trying to design this drug in such a way that it exploits evolution.”

The receptor in question is called angiotensin-converting enzyme 2, or ACE2, and the drug is an ACE2 receptor decoy. Known at this point as DF-COV-01, it has so far only been tested on animals.

In these experiments, coronavirus-infected hamsters who did not receive the treatment lost around 10% of their body weight – a measure of the severity of their infection – in the first five days. In contrast, infected hamsters that received the drug lost less weight and gained it back faster. The treated hamsters also had lower viral loads in their lungs.

Several research teams have pursued a strategy of deploying decoys to disrupt SARS-CoV-2 virus infection, said Jun Wang, a professor of medicinal chemistry at Rutgers University. But while “the idea is simple,” he said, “the devil is in the details,” and none have yet come to fruition as COVID-19 therapy.

Decoys cannot be packaged like pills that a patient might take at home, as they are protein and will not survive a trip through the gastrointestinal tract. Instead, they should be given either by injection or intravenously.

That said, “this paper has made a lot of progress” in advancing the prospects for using such therapy, Wang said. The researchers made modifications to the decoy molecule so that it could survive for 52 hours in the body of a mouse. If the same were true in humans, it could mean that the experimental therapy should be given every other day rather than daily.

From the patient’s perspective, “that’s a big plus,” he said.

But it’s not yet clear whether the improvements seen in hamsters will translate to humans.

“I was excited when I first read the article,” said Dr. Paul Insel, a pharmacologist at UC San Diego, who raised the possibility of ACE2 decoys as potential COVID treatments early on. of the pandemic. But then he became “discomfited when I actually looked at the results”.

“Even though there’s a lot of elegant science in this paper,” he added, “it’s not really biologically meaningful.”

The study authors acknowledged that the reduction in viral load was modest. But they pointed out that their results are similar to those seen in animal antibody studies that have been successful in humans.

This “bodes well for its likelihood of achieving a similar therapeutic effect in humans, but with the added benefit of long-lasting efficacy in the context of an ever-evolving virus,” they wrote.

The appeal of the decoy approach grew as the coronavirus exploited its penchant for mutation. Throughout the pandemic, the virus has undergone prolific changes, particularly in the structure of the spike protein it uses to enter a cell and infect its victims.

But while the virus has changed, the guiding beacon it looks for in human cells – the ACE2 receptor – has not. That means the experimental drug should work equally well regardless of how the coronavirus mutates, and the study suggests it does, Wang said.

Changes in the shape of the virus have increased the need for more resistant treatment. The BQ.1 and BQ.1.1 subvariants, which account for nearly two-thirds of coronavirus samples currently circulating in the United States, are resistant to all currently available monoclonal antibody treatments. In the early stages of the pandemic, these drugs were vital for unvaccinated patients and for immunocompromised patients who do not produce enough antibodies in response to vaccinations to protect them against serious disease.

Cancer researchers have been most active in developing decoy therapies, said Dr. Timothy J. Cardozo, professor of biochemistry and molecular pharmacology at NYU’s Grossman School of Medicine. Their goal was to trick cancer-fighting growth molecules into binding to decoys, thereby blocking the signals that fuel the uncontrolled growth of malignant cells.

This research has yielded a host of useful drugs, primarily for mitigating inflammation in autoimmune diseases, Cardozo said. He called the use of decoys to block viruses “fairly new” and said researchers’ focus on the ACE2 receptor makes it a “promising” way to block or limit a rampant infection.

But Cardozo cautioned that since ACE2 receptors appear in many different tissues and play various signaling roles, researchers will need to proceed with caution. The natural function of ACE2 is to modulate blood pressure, and Torchia modified the decoy version precisely so that it does not influence blood pressure, a common concern with this type of protein drug.

The team is currently working on the preclinical studies needed to begin human trials in 2023, Torchia said.

ACE2 is the target site of many other coronaviruses found in humans and – especially – non-human mammalian hosts. If the ACE2 decoy approach works, it could serve as a ready form of treatment against any other coronavirus that makes the leap across species, Torchia said.

“This viral transmission between species … may increase over time as climate and land use changes continue globally,” he said. “We really want to be much more prepared going forward.”