Researchers at MIT and the University of California, Santa Barbara, have identified compounds that activate a defense pathway inside cells infected by a virus. They believe these compounds could be used as antiviral drugs that will work against any virus. They published their findings in the journal Cell.
Researchers at MIT and other institutions have discovered broad-spectrum antiviral compounds through the use of a novel optogenetic screen, symbolized in this image by a beam of light piercing a virus. Credit: Kendall Pata, Type A Creative; edited by MIT News
The compounds activate a defense system called the integrated stress response pathway, which is triggered by double-stranded RNA produced during a virus’s replication, causing the cell to shut down protein synthesis and block the virus from replicating.
By boosting this pathway, the team hopes to develop a universal antiviral therapy. The researchers tested potential compounds against 370,830 molecules, demonstrating that these compounds are effective against RSV, herpes virus and Zika virus infections. The researchers also showed that the compounds were effective in fighting herpes infection in mice.
“These compounds robustly amplified diverse ISR stressors in cells. This unique behavior led us to characterize them as a new class of molecules, i.e., ‘ISR potentiators,’” said Max Wilson, Ph.D., Co-Founder and Chief Scientific Officer of Integrated Biosciences, where ISR is an abbreviation for integrated stress response.
A new class of broad-spectrum antivirals
“Typically, you develop one antiviral for one specific virus,” said Felix Wong, a former MIT postdoc and chief executive officer of Integrated Biosciences, the lead author of the paper. “In this case, we hypothesized that being able to modulate the host cell stress response might give us a new class of broad-spectrum antivirals — compounds that directly act on the host cells to alter something fundamental about how all viruses replicate.”
In order to identify these compounds, the researchers created a new optogenetic screen, a bioengineering technique in which scientists insert light-sensitive proteins into the genome of a cell. The researchers engineered modifications to a protein called PKR, which turns on the integrated stress response pathway, so that they could turn the protein on with a blue light. They used this technique to screen a library of 370,830 chemical compounds.
The researchers measured the cells’ survival rates to determine which compounds boosted the stress pathway and increased the cells’ ability to shut down viral replication. This yielded 3,500 potential compounds, which were then evaluated further. Finally, the team came up with three top contenders.
“Targeting the host enables broad-spectrum antiviral activity: by amplifying the host cell’s stress response to a wide range of viruses. Because host pathways mutate far less rapidly than viral genomes, this approach also theoretically reduces the potential for resistance,” said Wilson.
“Preparedness for emerging threats is another key advantage: host-directed therapies can serve as ‘off-the-shelf’ solutions during outbreaks, even before virus-specific drugs or vaccines are available. Crucially, they can be used alongside traditional antivirals for synergistic effects or when virus-targeted treatments are ineffective,” he added.
Fighting viral infections
In cells that were infected with Zika virus, herpes virus or RSV, the compounds significantly reduced the amount of virus in the cells. The researchers also tested one compound in mice infected with the herpes virus, finding that it was able to reduce the presence of the virus and improve symptoms. In mice, they found an approximate 20% average decrease in the levels of a chemokine (CXCL10/IP-10), expressed during herpes infection, with one of the compounds compared with a control group.
The compounds work by turning on an enzyme that is involved in detecting stress, activating the pathway. When applied to cells that are not infected by a virus, the compounds have no effect.
“The discovered compounds demonstrate broad-spectrum antiviral activity, showing efficacy against both single-stranded RNA viruses (Zika and respiratory syncytial virus) and a double-stranded DNA virus (herpes virus),” said Wilson.
The researchers plan to continue to test their compounds against more viruses and identify additional compounds that activate the pathway, as well as other pathways with the potential to help fight infections.
The research was funded by the Defense Threat Reduction Agency, the National Science Foundation, the U.S. Army Research Office, and Integrated Biosciences.
