Investigators at MIT and various institutions have discovered substances that can combat viral infections by triggering a defense mechanism within host cells. They anticipate that these substances could serve as antiviral medications effective against a wide range of viruses, not just one.
The team pinpointed these substances, which activate a defense mechanism in host cells known as the integrated stress response pathway, through a screening of nearly 400,000 molecules. Tests conducted in human cells demonstrated that these substances assist in fending off infections from RSV, herpes virus, and Zika virus. They also showed success in countering herpes infections in a mouse model.
The research team now intends to investigate the compounds against additional viruses, with the hope of advancing them towards eventual clinical trials.
“We’re extremely enthusiastic about this research, which allows us to exploit the stress response of host cells to find and develop broad-spectrum antivirals,” states James Collins, the Termeer Professor of Medical Engineering and Science at MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering.
Collins and Maxwell Wilson, an associate professor of molecular biology at the University of California, Santa Barbara, and chief scientific officer at Integrated Biosciences, are the senior authors of the recent study, which is published in Cell. Felix Wong, a former MIT postdoctoral researcher and CEO of Integrated Biosciences, leads the paper. Alongside MIT, UCSB, and Integrated Biosciences, the research team includes scientists from Illumina Ventures and Princeton University.
Enhancing cell defense
In human cells, the integrated stress response pathway activates in reaction to viral infection and other stressors like starvation. During viral infections, this pathway is initiated by double-stranded RNA, a molecule formed during the replication phase of viruses. Upon detection of this RNA, the cell inhibits protein synthesis, preventing the virus from creating the proteins essential for replication.
The researchers believe that substances amplifying this pathway could be excellent candidates for new antiviral drugs capable of tackling any virus type.
“Generally, antiviral drugs are developed targeting one specific virus,” Wong explains. “In this case, we theorized that modulating the host cell stress response could lead us to a new category of broad-spectrum antivirals — substances that directly interact with host cells to alter fundamental aspects of how all viruses replicate.”
To help identify compounds that would enhance the effectiveness of this pathway during viral infections, the researchers created a unique optogenetic screening method. Optogenetics is a bioengineering technique that enables researchers to incorporate light-sensitive proteins into a cell’s genome. In this study, the researchers engineered modifications to a protein named PKR, which activates the stress pathway, allowing them to trigger it with light.
Utilizing this approach, the researchers screened a collection of nearly 400,000 commercially available and proprietary chemical compounds. Each compound was applied to human cells while they were exposed to blue light, simulating viral infection by activating PKR.
By assessing the survival rates of the cells, the researchers could identify which compounds enhanced the pathway’s activation and improved the cells’ capability to suppress viral reproduction. This screening identified around 3,500 compounds with potential antiviral properties that were further evaluated.
“If the pathway is activated in response to a viral infection, what our compounds do is fully activate it,” Wong states. “Even with a minimal viral presence, if the pathway is engaged, the antiviral response is also maximally enhanced.”
Combating infection
The researchers then chose eight of the most promising compounds and evaluated their efficacy in eliminating viruses while minimizing harmful effects on human cells. From these tests, they selected three leading candidates, designated as IBX-200, IBX-202, and IBX-204.
Treatment with these compounds substantially decreased the viral load in cells infected with Zika virus, herpes virus, or RSV. The researchers subsequently tested one of the compounds, IBX-200, in mice infected with the herpes virus and discovered it successfully diminished the viral load and alleviated symptoms.
Experiments indicated that these compounds seem to activate an enzyme involved in stress detection, which initiates the stress response pathway and prepares the cells to better respond to viral infections. When administered to non-infected cells, the compounds have no observable effect.
The researchers now plan to test their lead candidates against a wider array of viruses. They also aim to discover more compounds that activate the integrated stress response, as well as other cellular stress pathways with the potential to eliminate viral or bacterial infections.
The research received funding from the Defense Threat Reduction Agency, the National Science Foundation, the U.S. Army Research Office, and Integrated Biosciences.