Drug Attacks Hepatitis B Virus Capsid

Researchers have recently made progress in developing new drugs to combat hepatitis B virus (HBV), according to a new study published by eLife.

Billions of individuals worldwide have been infected with HBV and millions are living with a chronic infection. Despite the creation of a vaccine, there is no cure for the liver disease.

In the new study, the researchers were able to determine how HBV changes its structure when it binds with an experimental antiviral drug currently being explored in clinical trials.

"Our discovery suggests that this same drug could attack hepatitis B virus on multiple fronts—both preventing replication and killing new copies of the virus," said senior author Adam Zlotnick, PhD. "If we're smart, we can take advantage of the multiple ways this drug can work at the same time."

Viruses replicate by hijacking a cell to produce more of the virus and protect its DNA and RNA by containing it in a capsid. The research team focused on studying the physics of how capsids are formed.

"The reaction is a bit like throwing a deck of cards in the air to build the Taj Mahal -- a highly complex structure seemingly emerging from chaos," Dr Zlotnick said.

The authors previously discovered a class of molecules that disrupt capsid protein assembly, called core protein allosteric modulators (CpAMs).

CpAM molecules cause the shells of viruses to assemble incorrectly, thus altering the life cycle of the virus; however, CpAMs were thought to only disrupt capsid formation after its DNA was already protected.

The new findings suggest that molecules can break apart the capsid after it has already been formed, according to the authors.

"The big implication is viral capsids aren't as impenetrable as previously thought," Dr Zlotnick said. “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.”

Through cryo-electron microscopy, the researchers discovered that the CpAM molecule was able to bend and distort the “soccer ball-shaped” capsid, according to the study.

Although this molecule is not included in ongoing clinical trials of CpAMs, these findings highlight the potential therapeutic power of the drug class, according to the study. The authors said they plan to conduct similar trials of this molecule in the future.

"About half of known virus families have soccer ball-like capsids; examples include polio and herpes," Dr Zlotnick said. "This study may lead to better treatments against them since the mechanisms behind capsid disruption could lead to drugs against any of them."