New antiviral class offers hope of halting rampage of treatment-resistant viruses and beyond

A totally new approach to antivirals may finally provide a solution to combating viruses that have evaded traditional therapy.

The current crop of herpesvirus drugs are designed to poison the machinery viruses use to multiply inside an infected cell. The only problem is that it doesn’t take long for the viral proteins targeted by these drugs to mutate just enough to render the therapies impotent.

Step forward, feedback disruptors—a class of therapy being developed by San Francisco’s Gladstone Institutes that have the potential to get around a virus’s mutation defence. The disruptors target and stop the genetic feedback loops that usually prevent viral proteins from becoming so toxic that they kill their host cells. With the link broken, the virus destroys the cells it relies on, bringing the infection to a screeching halt.

The latest breakthrough follows a previous discovery in the lab of Leor Weinberger, Ph.D., director of the Center for Cell Circuitry at Gladstone, where the feedback loop in cytomegalovirus (CMV), a common type of herpesvirus, was studied. The researchers noted that once a protein called IE86—needed for the virus to multiply—reaches high enough levels that it could start to become toxic for a cell, it switches off its own production until its concentration subsides and stabilizes.

In lab experiments, Weinberger and his team introduced genetic alterations to “cut the brakes” on this feedback loop, allowing IE86 production to rocket and destroy infected cells before the virus could replicate itself.

“It’s counterintuitive, because we’re ramping up production of a viral protein, but ultimately this counteracts infection instead of worsening it,” said Sonali Chaturvedi, Ph.D., who co-led the latest research with Weinberger, in a statement.

While all it takes are some small mutational adjustments for herpesviruses to outmaneuver traditional antivirals, responding to feedback disruptors is a far bigger challenge for these viruses.

“This study shows that resistance to feedback disruptors requires the virus to make numerous mutations at multiple different genomic locations, to essentially reconstitute a new feedback circuit,” Weinberger said. “The likelihood of this occurring is vanishingly small and lab experiments recapitulated this; the virus had little problem evolving resistance to current antivirals, but was unable to evolve resistance to feedback disruptors.”

To create a drug that could put this theory into practice, the researchers developed a small piece of synthetic DNA that binds to IE86 and prevents it from blocking its own production. Tests showed that this drug was effective against CMV in cells for many months without the virus ever developing resistance, they explained in a paper published May 12 in the journal Cell.

The drug's potential didn't end at CMV. Herpes simplex virus 1 (HSV-1), the leading infectious cause of blindness, was also shown in mice tests to be unable to withstand the new treatment. In fact, the researchers were even able to develop a feedback disruptor against the COVID-19 virus.

“This is very encouraging because it suggests that the feedback-disruptor strategy is not limited to DNA-based viruses like CMV and HSV-1, but can also be designed for RNA viruses like SARS-CoV-2,” Chaturvedi said.

The team has even bigger ambitions for its discovery, including investigating whether feedback loops could be targeted to cancer or bacterial diseases. Further lab studies in herpesviruses could also pave the way for bringing their CMV drug to the clinic.

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