Many known viruses pose a continuing threat to public health, and we are constantly dealing with the possibility that new viruses could emerge to cause more health problems. We also seem to lack a wide arsenal of antiviral drugs. But new research may help change that. Scientists have conducted a large compound screen and revealed many potential new antiviral drugs. These drugs could be useful not against a single virus, but against many different viruses, because they can boost a defense mechanism in human cells. The findings have been reported in Cell.
After searching through about 400,000 molecules, scientists have determined that many are useful in stopping RSV, herpes virus, and Zika virus infections.
“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,” noted James Collins, a Professor at MIT.
Human cells can activate the integrated stress response pathway due to various problems, such as starvation, or viral infection. The replication of RNA viruses generates double-stranded RNA molecules that can trigger this pathway. Cells stop synthesizing proteins when this happens, to stop viral replication. The researchers are hopeful that drugs that boost this process could make effective antivirals.
“Typically, how antivirals are developed is that you develop one antiviral for one specific virus,” said first study author Felix Wong, PhD, chief executive officer 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.”
The researchers used optogenetics, in which light can modify gene activity, in their screen. The PKR protein, which activates the targeted stress response, was modified to be turned on with light.
The team looked at 400,000 compounds in human cells that were exposed to light, which was meant to activate PKR. There were about 3,500 cells that survived this process since were accompanied by a compound that boosted the pathway's activation.
“If the pathway were turned on in response to viral infection, what our compounds do is they turn it on full blast,” Wong explained. “Even in the presence of a small amount of virus, if the pathway is triggered, then the antiviral response is also maximized.”
Eight of the best compounds were chosen for further study. The researchers found that the amount of virus was significantly lowered after infected cells were exposed to these compounds. One in particular was able to fight herpes in a mouse model of infection as well.
Now the researchers are planning to conduct more tests with different viruses, and evaluate and conduct additional evaluations and improvements of these compounds. They are also still looking for new antivirals.
