Disrupting a virus’s genome packaging can halt replication, study finds

Like savvy international travelers, viruses know exactly how to pack. With the genetic instructions for the next generation folded just so, snuggled into a custom-made outer covering studded with cell-grabbing proteins, these tiny invaders quest for new digs on the reg. When they find them, they get to work. Each newly infected cell soon releases thousands of perfectly packed, fresh-faced viral particles — fueling an infection's exponential growth.

Now a Stanford Medicine study of influenza and of SARS-CoV-2 — the virus that causes COVID-19 — shows that antiviral drugs that disrupt this game of genomic Tetris can bring infections to a screeching halt. At the same time, these drugs allow just enough exposure to the virus to jumpstart a natural immune response that confers lasting protection.

Because tried-and-true packing strategies are shared among viral family members, one antiviral drug can be effective against several closely related viruses, such as seasonal influenza A, swine flu and bird flu. And because it's difficult to rejigger a three-dimensional puzzle, viruses are unlikely to become resistant to a treatment that harnesses this tactic.

These antivirals can be tailored to nearly any virus. They provide immediate protection when administered either prior to or after exposure, and they stimulate a lasting immune response that neutralizes a subsequent challenge of even a tenfold lethal dose of influenza. This is really exciting."

Jeffrey Glenn, MD, PhD, professor of microbiology and immunology

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The study, which was conducted in mice, hamsters and human cells grown in the laboratory, was published online in Nature Medicine Aug. 18. Glenn, the Joseph D. Grant Professor II, is the senior author of the study. Research scientist Rachel Hagey, PhD, is the lead author of the paper.

A tool for the next pandemic

The discovery suggests the possibility of quickly dampening the spread of some of humankind's deadliest viruses with off-the-shelf custom antivirals designed, manufactured and stockpiled before the next outbreak occurs.

The findings are the first to come out of Stanford's newly formed SyneRx, which is one of nine Antiviral Drug Discovery Centers for Pathogens of Pandemic Concern funded by the National Institute for Allergy and Infectious Diseases, and [email protected], which is Stanford Medicine's Biosecurity and Pandemic Preparedness Initiative. Glenn leads the center, which received $69 million in May to help design antivirals to combat COVID-19 and other diseases with the potential to cause future pandemics.

Vaccines that fight viruses typically encourage the body's immune system to recognize and react to critical viral proteins, such as the spike protein of SARS-CoV-2. But, as has become obvious during the ongoing pandemic, proteins can mutate in subtle ways to evade the immune system, leading to breakthrough infections in vaccinated people.