Amazing stuff! The systematic discovery of antivirals makes further progress.
"Researchers ... have identified compounds that can fight off viral infection by activating a defense pathway inside host cells. These compounds, they believe, could be used as antiviral drugs that work against not just one but any kind of virus.
The researchers identified these compounds, which activate a host cell defense system known as the integrated stress response pathway, in a screen of nearly 400,000 molecules. In tests in human cells, the researchers showed that the compounds help cells fend off infection from RSV, herpes virus, and Zika virus. They also proved effective in combating herpes infection in a mouse model. ...
By measuring the cells’ survival rates, the researchers could determine which compounds boosted activation of the pathway and amplified the cells’ ability to shut down viral reproduction. This screen yielded about 3,500 compounds with potential antiviral activity, which were evaluated further. ..."
From the highlights and abstract:
"Highlights
• An optogenetics platform specifically induces the integrated stress response
• This platform enables a high-throughput screen of 370,830 compounds
• Identified compounds selectively eliminate ISR-high cells across diverse stressors
• These compounds demonstrate broad-spectrum antiviral activity in vitro and in mice
Summary
The integrated stress response (ISR) is a conserved stress response that maintains homeostasis in eukaryotic cells.
Modulating the ISR holds therapeutic potential for diseases including viral infection, cancer, and neurodegeneration, but few known compounds can do so without toxicity.
Here, we present an optogenetic platform for the discovery of compounds that selectively modulate the ISR. Optogenetic clustering of PKR induces ISR-mediated cell death, enabling the high-throughput screening of 370,830 compounds.
We identify compounds that potentiate cell death without cytotoxicity across diverse cell types and stressors. Mechanistic studies reveal that these compounds upregulate activating transcription factor 4 (ATF4), sensitizing cells to stress and apoptosis, and identify GCN2 as a molecular target.
Additionally, these compounds exhibit antiviral activity, and one compound reduced viral titers in a mouse model of herpesvirus infection. Structure-activity and toxicology studies highlight opportunities to optimize therapeutic efficacy. This work demonstrates an optogenetic approach to drug discovery and introduces ISR potentiators with therapeutic potential."
Optogenetics-enabled discovery of integrated stress response modulators (no public access)
Graphical abstract
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