Breaking Hepatitis C's Shell

Professor Donny Strosberg

Donny Strosberg went from fame in France to relative obscurity in the United States because, like many good scientists, he couldn't say "no" to a problem that posed both an incredible intellectual challenge and an opportunity to impact millions of lives.

The challenge? Finding a better treatment for hepatitis C virus (HCV), which has infected more than 130 million people around the world and, along with hepatitis B, is the main cause of liver cancer.

One of the main reasons HCV defies drugs is that it mutates quickly, often causing patients to become drug resistant.

Strosberg saw an opening, though, in reactions between the virus's proteins.

"Everybody said [it] would never work," Strosberg said. But Scripps Research was willing to take the risk.

In 2005, Strosberg left France for Scripps Florida. This winter, his team described several small molecules that could make promising drug candidates by inhibiting a chemical process involving the core protein that's important to the virus's ability to mutate.

"The fact that is so exciting is that no one has really considered the core protein as a viable target in HCV," Strosberg said. "With this study, there is now no good reason why researchers shouldn't go after the HCV core protein."

The core protein is so critical because it orchestrates the assembly and release of the infectious virus, and also the disassembly of viral particles upon entering host cells.

The chemical process Strosberg targeted is one that is essential to the survival of the virus, where the core protein binds to itself and related proteins to form the viral capsid. Like an eggshell protects its yolk sack, the capsid is an outer encapsulated protein shell that protects the virus's genetic material.

Strosberg's team started by finding a way that peptides (two or more amino acids that are the building blocks of proteins) derived from the HCV core protein could inhibit this key chemical process.

It was an important proof-of-concept, but it had limited applicability since peptides are difficult to use in oral drugs and are unstable in circulating blood.

So, Strosberg's team dug further, looking for small molecules with the potential to disrupt the virus in the same way.

Taking information they gained from their peptide study, they were able to uncover a section of the core protein – what they called "a hot spot" – that was essential for the interaction that creates the capsid and allows the virus to function.

Then they developed a highly efficient test that allowed them to test 2,250 compounds, looking for ones that could disrupt the key critical process the way the peptides had.

That screening found four promising compounds.

"While there is no similarity structurally between these new small molecule inhibitors and the peptides, functionally they behave precisely the same way," Strosberg explained. "These new compounds definitely put us closer to the 'El Dorado' of finding viable protein-protein inhibitors for HCV."