‘Virus-cracking’ molecules

Indiana University team fights hepatitis B

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BLOOMINGTON, Ind.—Globally, about two billion people have had a hepatitis B virus (HBV) infection in their lifetime, and more than 240 million live with chronic infection. While a vaccine exists, there is no cure.
Adam Zlotnick, a professor in the Indiana University Bloomington College of Arts and Sciences’ Department of Molecular and Cellular Biochemistry, whose research team has made an important step forward in the design of drugs that fight the hepatitis B virus, explained, “HBV is a deadly disease. More than 700,000 people die each year from HBV. Chronic HBV patients are at much greater risk of liver cancer, cirrhosis and liver failure. They are also at risk of passing the virus on to others.”
Zlotnick added, “There is a great vaccine for HBV. Every infant should be vaccinated. There are medicines available that will suppress the virus. These ‘nucleoside analogs’ block the viral reverse transcriptase. They can improve liver health, but they have little effect on curing a chronic patient. A safe and effective medicine that cures the patient—no virus or viral proteins in the blood—would save this generation’s chronic HBV patients and prevent a next generation of HBV patients.”
The researchers published a study in the January 29 issue of the journal eLife explaining how the structure of the hepatitis B virus changes when bound to an experimental drug. Members of this new class of antiviral drug are now in clinical trials.
According to Zlotnick, “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. If we’re smart, we can take advantage of the multiple ways this drug can work at the same time.”
A physical biochemist fascinated by virus self-assembly, Zlotnick said he started working on virus assembly as a graduate student, almost 30 years ago. The approach he took starts with fundamental biophysics that can be applied to a problem of human health. As he explained, “About half of known virus families have a spherical shell, or capsid. For hepatitis B virus, and many other viruses, you can take purified capsid protein, adjust solution conditions, and the protein will spontaneously assemble. The results usually look exactly like the native virus. After showing how we could observe HBV assembly, I became interested in how we could perturb assembly.”
He recalled that at the same time, Bayer published a paper showing that it had a drug that affected HBV in a capsid-dependent manner. While Bayer did not have a mechanism, Zlotnick’s colleague MG Finn synthesized an analog for him. They showed that the molecule sped up assembly, strengthened protein-protein interactions and interfered with normal interaction geometry.
“Since then we have been trying to get a better handle on mechanism and drug design,” Zlotnick said. “While the structure we just published is based on one particular chemical scaffold, we have developed approaches for screening chemical libraries, as have other groups, so we know there are several different chemistries that look really promising. As a group, we call the HBV assembly-activating molecules core protein allosteric modulators—CpAMs for short.”
A virus reproduces by hijacking a host’s cellular machinery to produce more of the virus. Most viruses protect their genetic material—DNA or RNA—inside the capsid. CpAMs disrupt capsid protein assembly by interfering with an enzymatic activity.
Zlotnick explained, “We are interfering with a protein-protein interaction. Normal HBV assembly is nucleated by a complex of viral RNA and reverse transcriptase. The drug can activate assembly on its own, an allosteric effect. By strengthening protein-protein interactions, they also drive more assembly and thus deplete the concentration of free core protein. By butchering normal capsid geometry, for newly assembly capsid protein and even when soaked into a pre-assembled capsid, the drug prevents the capsid from doing its jobs: protecting the viral genome, serving as a compartment for reverse transcription and interacting with other host and viral proteins. The HBV core protein has many functions, and so CpAMs have the opportunity to interfere with multiple steps in the virus lifecycle.”
The IU scientists bound the CpAM to a chemical called TAMRA to make it fluorescent and easier to detect in experiments. Using cryo-electron microscopy, they found the small CpAM molecule could make the large, soccer ball-shaped virus capsid bend and distort.
“The big implication is viral capsids aren’t as impenetrable as previously thought,” Zlotnick noted. “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. About half of known virus families have soccer ball-like capsids; examples include polio and herpes. This study may lead to better treatments against them since the mechanisms behind capsid disruption could lead to drugs against any of them.”
According to Zlotnick, many large pharmaceutical companies and startups are working on CpAMs, which are attractive because they “definitely suppress viruses in tissue culture and in clinical trials.” There are also groups working on other targets including viral entry and viral RNase H. Several companies—including a company Zlotnick co-founded, Assembly BioSciences—have CpAMs in clinical trials.
Zlotnick opined, “Bringing medication to where it is needed is an overwhelming problem. I work on a much simpler problem: I can help design and test approaches for making the medication.”

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