Cryo-EM Advances Fight Against Hepatitis B

Indiana University researchers used cryo-electron microscopy to make an important step forward in the design of drugs that fight the hepatitis B virus, known to cause liver failure and liver cancer. A vaccine exists, but there is no cure. The study explains how the structure of the hepatitis B virus changes when bound to an experimental drug, suggesting that the new drug could both prevent replication and kill new copies of the virus.

“Our discovery suggests that this same drug could attack hepatitis B virus on multiple fronts,” says Adam Zlotnick, a professor in the IU Department of Molecular and Cellular Biochemistry and senior author of the study published in the journal eLife. “If we’re smart, we can take advantage of the multiple ways this drug can work at the same time.”

It’s estimated that two billion people worldwide have had a hepatitis B virus infection in their lifetime, with about 250 million—including two million Americans—living with chronic infection. Like other viruses, it reproduces by hijacking a host’s cellular machinery to produce more of the virus. The majority of viruses protect genetic material—DNA or RNA—inside a protein shell called a “capsid.” For the past 20 years, Zlotnick’s lab has conducted research to stop viral infections by studying the physics of viruses, focusing on how capsids are formed.

Researchers at the lab helped discover a class of molecules called core protein allosteric modulators, or CpAMs, that disrupt capsid protein assembly. CpAM molecules attack viruses by causing their shells to assemble incorrectly, interrupting the life cycle of the virus. Previously, CpAMs were seen as only able to disrupt a virus during formation of the capsid, after which its DNA was protected inside a hard casing.

The new study, led by graduate student Christopher Schlicksup, found that the molecule can break apart this shell even after it has already assembled. To make the discovery, the IU team bound the CpAM to a chemical called TAMRA—a crimson-colored dye used in some red lipstick—to make it fluorescent and easier to detect in experiments. Using cryo-electron microscopy, the researchers found the small CpAM molecule could make the large, soccer ball-shaped virus capsid bend and distort.

About half of the known virus families have soccer ball-like capsids, including polio and herpes, so the study may lead to better treatments against them, since the mechanisms behind capsid disruption could lead to drugs against any of them. “The big implication is viral capsids aren’t as impenetrable as previously thought,” Zlotnick says. “The other implication, which may be even more important, is that if this type of interference works against hepatitis B virus, it might also work against other viruses.