Developing drugs to eradicate the hepatitis B virus
When Adam Zlotnick started an independent lab in 1997, studying the physics of viruses was considered esoteric. Basic research into the kinetics and thermodynamics involved in how viruses form and replicate was not seen by the scientific community as a direct path to developing antiviral compounds.
Such sentiments were readily shared by Zlotnick's peers when he first sought funding from the National Institutes of Health and the American Cancer Society.
"One of the reviewers wrote that 'this might have been fascinating 20 years ago, but I can't see where it's going,'" said Zlotnick, a professor of molecular and cellular biochemistry at IU Bloomington. "But I was very fortunate that the American Cancer Society at that time focused its research dollars on young researchers willing to think outside the box. So some of its reviewers thought my ideas were a good gamble."
Nearly two decades after winning the confidence of the cancer society and the NIH as well, Zlotnick is helping reshape the way that scientists attack certain viral diseases.
To exploit leverage points in the capsid assembly of the hepatitis B virus, or HBV, Zlotnick and William Turner, a medicinal chemist and former IU visiting scholar, began to develop molecules that altered HBV assembly.
Hepatitis B is a major cause of liver failure and liver cancer that annually kills more than 500,000 people worldwide. Although it is preventable by vaccine, more than 240 million people—including 2 million Americans—suffer from chronic HBV. Areas hardest hit include sub-Saharan Africa and parts of East Asia, where 5 percent to 10 percent of the population have the disease.
Eventually this work led Zlotnick, Turner, and three other colleagues to found Assembly Pharmaceuticals to develop curative therapies for the disease. By late 2014, Assembly had merged with a Nasdaq-listed biotech firm to become Assembly Biosciences. Along with its HBV work, Assembly is pursuing an integrated microbiome program to address diseases of the gastrointestinal tract.
An important test for Assembly arrives later this year, when the company is expected to begin clinical trials on its lead HBV drug. What makes this drug different? Unlike traditional approaches that target enzymes, a process that controls—rather than kills—the virus, Assembly's compound is designed to send parts of the viral replication process into overdrive.
The principle stems from key observations into the physics and physical chemistry of viruses, Zlotnick said. First, a stable capsid, the protein "shell" of a virus that encloses its genome, is based on weak rather than strong interactions. Second, it is hard to stop spontaneous capsid assembly of new viruses once it has started, and it is easy to encourage viral growth—so long as all the right components are in place.
"With each assembly step, the growing virus becomes more and more stable. So if you think of that assembly reaction with a small virus like hepatitis B, you have minimally 122 components. And it assembles in a matter of seconds. If you have assembly running at the right speed, you can get the right kind of capsid with all the right components," Zlotnick said.
With each assembly step, the growing virus becomes more and more stable ... But like any assembly line, if you speed it up, you start to get errors.
"But like any assembly line, if you speed it up, you start to get errors," he explained. "If you speed it up by a factor of two, you’ll get more viruses. But speed it up by, say, a factor of 1,000, and it's like taking an assembly line that normally runs at half a mile an hour and getting it up to 500 mph. In one case, you get cars. In the other, you would be lucky to get a steering wheel."
Hepatitis B is a more-than-formidable adversary. Often referred to as a stealth virus, it looks and acts like human chromatin and can even turn off the host's immune response, Zlotnick said. So elusive is HBV that a Nobel Prize was awarded in 1966 just for its discovery.
Of course, one scientist alone cannot develop a drug and take it all the way to market, thus the establishment of Assembly Pharmaceuticals in 2012. Along with his IU duties, Zlotnick serves as Assembly's chief scientific adviser for virology.
Several other members of the Assembly team have IU or Indiana ties. They include Turner, who heads up discovery chemistry for the company, and Richard DiMarchi, an experienced entrepreneur and Assembly director who serves as the Cox Distinguished Professor of Biochemistry and Gill Chair in Biomolecular Sciences at IU Bloomington. Co-founder and CEO Derek Small is an Indiana native.
The company has administrative offices near Indianapolis, plus research and development facilities in Bloomington and San Francisco and an investor relations office in New York City.
"As we [Zlotnick and Turner] started to develop a better library of molecules … I realized how little I knew about the subsequent testing that has to happen. So I wound up talking with Richard DiMarchi about what was needed to put together a company. Once he was convinced that I was committed, he introduced me to Derek Small," Zlotnick said.
"One of the points that Richard made was if I wanted to go this route, I would have to be dedicated not only to my academic research, but also to supporting the research end of the company," he continued. "So while Assembly started with some understanding of the physics of virus assembly, molecule development has to follow the disciplines of pharmacology and medicinal chemistry. I can spell those, but I can't do them.
"Assembly now has leadership from scientists with extensive expertise in drug development, and my contribution focuses on my strengths in virology, biochemistry, and biophysics," he said.
Whether or not Assembly achieves its mission to cure HBV, Zlotnick said, he will remain a firm believer in the value of pursuing basic research.
"If my basic research makes it into textbooks, that's great. I'm helping train people I've never met," he said. "But some of that basic research and some of the applied research that stems from it are changing the way people look at how to develop antivirals.
"Without the basic research underpinning the effort, and the funding for that basic research, this endeavor would be science fiction."