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Researchers at Harvard’s Wyss Institute for Biologically Inspired Engineering have developed a broad-spectrum drug that can target a range of coronaviruses using physics-driven modeling — a process that drew on artificial intelligence tools and took a page from Hollywood.
Researchers will continue to work to test the drug’s efficacy and eliminate the possibility of off-target effects, but the compound holds “great potential for fighting future respiratory pandemics,” according to a Thursday statement from the Wyss Institute.
“Our findings are extremely compelling and open up a new path for dealing with viral outbreaks,” former Wyss Institute Principal Scientist Charles Reilly wrote in the press release.
Reilly led the project with Wyss Founding Director Donald E. Ingber, who said researchers’ goal of creating the drug set a high expectation for the team.
“By aiming for an orally available drug that broadly inhibits multiple coronaviruses, even as a prophylactic treatment, we deliberately set the bar at maximum height,” Ingber, a professor at Harvard Medical School and the School of Engineering and Applied Sciences, wrote in the Thursday press release.
The researchers identified bemcentinib — a compound that is currently being clinically tested as a cancer treatment — as a potential antiviral agent. They used the drug as a “launch pad” to develop WYS-694, a compound that they say is more specific and effective against a broad range of coronaviruses.
Even years after the height of the initial Covid-19 pandemic, the virus continues to mutate to resist antiviral drug treatments, giving rise to outbreaks of variants and subvariants like Omicron and Delta. Coronaviruses are the cause of 30 percent of all respiratory tract infections, leading to widespread illnesses and outbreaks, and underscoring the need for more accessible treatment.
In the press release, the Wyss Institute said that new treatments are especially important because access to prophylactic vaccines is unequal and vaccine hesitancy may slow adoption.
While there are existing antiviral drugs and vaccines, access to these treatments can be limited, the researchers said. Other broad-spectrum coronavirus treatments like Paxlovid and Lagevrio first hit the market in 2023, though they are more limited in the range of viruses they target.
Because of this, the research team said that finding a new treatment like WYS-694 — one that could be fast-acting, easily distributable, and effective against multiple respiratory coronaviruses — is essential.
The team identified their new compound with a hybrid approach to modeling molecules, combining traditional physics-based modeling with AI enhancements and film industry animation software.
Animation software, like Blender and Autodesk, are often used in the film industry to render graphics and model interactions between objects — functions that researchers have repurposed to visualize and simulate molecular interactions.
Ingber praised Reilly as the “brains” behind using the animation software for molecular modeling. Reilly learned animation when he worked for Peter Jackson, producer of the Lord of the Rings trilogy, Ingber said.
“We had a paper where he first combined approaches — a pipeline from the animation industry with scientific softwares,” Ingber said in a Thursday interview.
“That’s totally his innovation,” Ingber added.
It was those computational models, derived from movie-making techniques, that let the team of researchers find the drug that would become an inspiration for WYS-694.
In order to transmit genetic material into human cells, causing symptoms, coronaviruses must latch onto the host cells and fuse portions of their cell membranes. A drug could block that process by preventing the virus from fusing with host cells.
Many efforts to develop coronavirus drugs have focused on external regions of the viruses’ spike proteins, which bind to host cells. But those regions are likely to mutate faster, because they are often targeted by treatments and vaccines, meaning that existing medications might lose their efficacy over time.
Instead, the Wyss Institute team aimed to create a drug that would bind to normally hidden regions of the virus’s spike proteins. That required complex simulations of the molecular changes that viruses undergo as they bind with cells and prepare to fuse cell membranes — and modified animation software proved well-suited to the task.
Then, the researchers screened roughly 10,000 existing drugs to find which ones best bound to their chosen site. After filtering to focus on treatments that are orally available, their winner was bemcentinib. Medicinal chemist Joel D. Moore developed a novel compound, WYS-633, with similar properties.
After more chemistry work, AI modeling, and in vitro testing, the team developed the stronger WYS-694 compound and tested it in mice infected with SARS-CoV-2, the virus that causes Covid-19. The new compound reduced the viral load in the mice fourfold.
While the development of the compound itself is significant, Ingber wrote in the press release that the technological approach used in their research “has proven to be incredibly powerful.”
“Beyond producing a promising new drug that could be useful in future respiratory pandemics, this approach holds great potential for the discovery of drugs against a number of other virus families utilizing membrane fusion proteins, including influenza, HIV, Ebola, Measles, and others,” Ingber wrote.
—Staff writer Megan L. Blonigen can be reached at megan.blonigen@thecrimson.com. Follow her on X at @MeganBlonigen.
—Staff writer Laurel M. Shugart can be reached at laurel.shugart@thecrimson.com. Follow them on X @laurelmshugart.
