Killer virus has a deadly sweet tooth

BROWN (US) — It doesn’t strike often but when the JC polyomavirus does, it’s ruthless. The virus preys on people with weakened immune systems and almost always kills them.

Now the killer may have a target on its back. An international team has uncovered that the virus must bind to a very specific sugar molecule dangling from the side of the brain cells it attacks.

The finding, reported this week in the journal Cell Host & Microbe, could provide a basis for developing drugs to interrupt that process.

Researchers from Brown University, the University of Tübingen in Germany, and Imperial College in London painstakingly characterized the precise structure and biology of how the virus binds to host cells down to the atomic level. By exposing a specific target, the work sets the table for drug development to begin, says Walter Atwood, professor of molecular biology, cell biology, and biochemistry at Brown and a senior author of the study.

“The overall goal is to get these ‘plans’ and then design small molecules—drugs that will fit in this receptor, binding and preventing infection,” Atwood says.

Atwood notes that this paper also marks the first time anyone has fully determined the structure and binding functionality of a human polyomavirus. While the JC polyomavirus causes the brain-wasting disease known as PML, others in the “family” are implicated in ailments such as skin cancers.

When the virus floats toward a cell, it encounters a metaphorical cityscape of sugary molecules on its surface, says Brown postdoctoral researcher Melissa Maginnis, one of the paper’s two lead authors. The team wanted to know which one the virus chooses.

To finger a suspect, they turned to the lab of Ten Feizi, professor of medicine at Imperial College in London. After extensive screening experiments, Feizi and researcher Angelina Palma found that the virus strongly preferred to bind to sialic acid on the end of a molecule called LSTc.

From there, the Tübingen team crystallized the virus capsid protein VP1 with LSTc for imaging with x-rays at atomic resolution and showed exactly how the virus and LSTc bind.

Meanwhile the team at Brown, conducted experiments in which they sought further biological proof that binding with LSTc made the crucial difference between infection and health.

In one experiment, they pre-mixed the virus in some cases with LSTc and in others with the very similar molecule LSTb. Then they exposed each to glial cells. The virus pre-mixed with LSTc did not infect the cells, because they had already bound to LSTc in incubation (like a child who ruins an appetite by snacking before dinner).

The virus that had been pre-exposed to LSTb, readily infected the glial cells. This told the researchers that the virus strongly “prefers” LSTc.

The team also created mutated versions of the virus’s binding protein to see whether any of the alterations would ruin is ability to infect cells. Different changes that made it more difficult for the virus to bind to LSTc also reduced the likelihood of infection to different degrees, showing that the binding to LSTc was what led to infection and also shedding light on the exact role each subpart plays.

The next step—finding a small-molecule drug that will cross the blood-brain barrier and bind to the virus so that it can’t bind with LSTc—is already getting under way in the Dartmouth College lab of Dale Mierke, who is a partner on the team’s grant from the National Institute of Neurological Disorders and Stroke.

For all the years they’ve put in, the researchers know they are still only in the middle of the fight.

“Drug development is a very long-term process,” Nelson says. “But the data in this paper provides the platform for rational drug design and opens the door to begin the process of screening compounds.”

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