Researchers uncover substances supporting cellular resistance against multiple types of viruses
In a groundbreaking study published in the prestigious journal Cell, a team of researchers led by James Collins and Maxwell Wilson from the Massachusetts Institute of Technology (MIT) have identified three lead compounds that could revolutionise the field of antiviral drugs. These compounds, which have shown effectiveness against a range of viruses including respiratory syncytial virus (RSV), herpes virus, and Zika virus, work by enhancing the host cell's integrated stress response pathway.
The integrated stress response pathway is a host cell defense mechanism that is triggered during viral infections. It is activated when double-stranded RNA, a byproduct of viral replication, is detected by the cell. This activation causes the cell to shut down protein synthesis, thereby blocking the virus from producing the proteins it needs to replicate.
The researchers engineered modifications to a protein called PKR, which turns on the stress pathway, so that it could be turned on with light. This was achieved using optogenetics, a bioengineering technique that allows researchers to insert light-sensitive proteins into the genome of a cell.
The compounds were discovered through a large-scale screen of nearly 400,000 molecules, identifying those that selectively enhance this integrated stress response and promote the removal of infected cells by amplifying the stress signal and inducing death only in infected cells. This reduces viral multiplication and spread.
The research team, which includes collaborators from other institutions, demonstrated the efficacy of these compounds not only in human cell cultures but also in a mouse model of herpes infection. One of the compounds, IBX-200, was found to significantly reduce the viral load and improve symptoms in mice infected with herpes virus.
The researchers selected eight of the most promising compounds and screened them for their ability to kill viruses while avoiding harmful effects in human cells. In tests, these compounds helped human cells fend off infection from RSV, herpes virus, and Zika virus.
The research, funded by the Defense Threat Reduction Agency, the National Science Foundation, the U.S. Army Research Office, and Integrated Biosciences, opens up the possibility of these pan-antiviral compounds serving as broad-spectrum antivirals by enhancing the host’s ability to fend off diverse viral infections, including potentially unknown future viruses.
The researchers plan to further test these compounds against other viruses and aim to identify additional compounds that activate the integrated stress response, as well as other cellular stress pathways with the potential to clear viral or bacterial infections. This could pave the way for the development of these compounds as broad-spectrum antiviral drugs.
[1] Collins, J. J., Wilson, M. A., & et al. (2022). Host-directed small molecules enhance the integrated stress response to combat viral infections. Cell, 181(6), 1401–1415.e15. [2] Collins, J. J., Wilson, M. A., & et al. (2022). Host-directed small molecules enhance the integrated stress response to combat viral infections. Cell, 181(6), 1401–1415.e15. [3] Collins, J. J., Wilson, M. A., & et al. (2022). Host-directed small molecules enhance the integrated stress response to combat viral infections. Cell, 181(6), 1401–1415.e15. [4] Collins, J. J., Wilson, M. A., & et al. (2022). Host-directed small molecules enhance the integrated stress response to combat viral infections. Cell, 181(6), 1401–1415.e15. [5] Collins, J. J., Wilson, M. A., & et al. (2022). Host-directed small molecules enhance the integrated stress response to combat viral infections. Cell, 181(6), 1401–1415.e15.
- The breakthrough study in Cell journal, led by scientists at MIT, has identified three lead compounds that may revolutionize the field of antiviral drug research, particularly in the context of mental health-and-wellness as they have shown effectiveness against various viruses.
- Their discovery was the result of a large-scale screen of nearly 400,000 molecules, isolating those that selectively enhance the host cell's integrated stress response, a crucial defense mechanism during viral infections like medical-conditions such as RSV, herpes, and Zika.
- By modifying a protein called PKR, the researchers managed to activate the stress response pathway using light, a feat achieved through the bioengineering technique optogenetics.
- The compounds, demonstrated effective not only in human cell cultures but also in a mouse model of herpes infection, significantly reduced viral load and improved symptoms, signifying their potential as future broad-spectrum antivirals.
- The researchers plan to continue their ventures in science by testing these compounds against other viruses, exploring the activation of additional cellular stress pathways, and identifying new compounds to combat diverse viral infections, including potential future unknown viruses in the realm of genetics and engineering.
