Scientists at MIT and other institutions identified compounds that activate the integrated stress response pathway in host cells, offering hope for new broad-spectrum antiviral drugs.
A team of researchers from MIT, in collaboration with other institutions, has made a groundbreaking discovery in the fight against viral infections. By identifying compounds that can activate a defense pathway within host cells, they may have unlocked a method to create antiviral drugs effective against a range of viruses.
The research, published in the journal Cell, promises to shift the paradigm of antiviral treatment.
“We’re very excited about this work, which allows us to harness the stress response of the host cells to arrive at a means to identify and develop broad-spectrum antivirals,” senior author James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering, said in a news release.
In a massive screen of nearly 400,000 molecules, the team discovered these compounds that activate the integrated stress response pathway. This pathway is a vital cellular defense mechanism against viral infection and other stressors.
When a virus infects a cell, double-stranded RNA produced during viral replication triggers this pathway, shutting down protein synthesis and preventing the virus from multiplying.
“Typically, how antivirals are developed is that you develop one antiviral for one specific virus,” added lead author Felix Wong, a former MIT postdoc and current CEO of Integrated Biosciences. “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.”
Using an innovative optogenetic screen they created, the researchers identified compounds that enhance the stress pathway during viral infections.
Optogenetics is a technique that uses light-sensitive proteins to control cellular functions, allowing precise control over cellular pathways. By exposing the engineered cells to light and testing the compounds, the team identified about 3,500 potential antiviral agents.
“If the pathway were turned on in response to viral infection, what our compounds do is they turn it on full blast,” Wong added. “Even in the presence of a small amount of virus, if the pathway is triggered, then the antiviral response is also maximized.”
From these candidates, the team selected three top compounds — IBX-200, IBX-202 and IBX-204 — that showed remarkable efficacy against Zika virus, herpes virus and RSV in cellular models.
They further tested IBX-200 in a mouse model of herpes infection, finding significant reductions in viral load and improvements in symptoms.
The next steps for the researchers involve testing the lead compounds against a broader spectrum of viruses and searching for additional chemicals that activate the integrated stress response and other cellular pathways against viral and bacterial infections.
The study included contributions from Maxwell Wilson, co-senior author of the study and an associate professor of molecular biology at the University of California, Santa Barbara and chief scientific officer of Integrated Biosciences, as well as scientists from Illumina Ventures and Princeton University.