Scripps Researchers Identify Novel Hepatitis C Inhibitors
News Dec 24, 2009
Scientists from the Scripps Florida campus of The Scripps Research Institute and their colleagues at Boston University have described their discovery of several novel drug-like inhibitors of the hepatitis C virus (HCV). These new inhibitors have the potential to substantially widen the current options to treat HCV infection.
The research, from the laboratory of Professor Donny Strosberg, Ph.D., of Scripps Florida, supported by members of the Scripps Florida Lead Discovery Division directed by Peter Hodder, Ph.D., and colleagues from Boston University, was published in the December 2009 edition of the journal ASSAY and Drug Development Technologies and appears in the December 15, 2009 print edition of the journal Bioorganic & Medicinal Chemistry Letters.
With more than 130 million people infected worldwide by HCV, new therapeutic strategies are urgently needed for this blood-borne disease, which is the main cause, with hepatitis B, of liver cancer, according to the National Cancer Institute.
Using a new fluorescence-based assay, the scientists were able to identify four small-molecule inhibitors of dimerization of the viral core protein. In this process, which is essential to the survival of the virus, the core protein binds to itself and related proteins to form the viral capsid, the outer lipid-encapsulated protein shell that protects the virus’s genetic material like an eggshell protects its yolk sack.
“The fact that is so exciting is that no one has really considered the core protein as a viable target in HCV—in HIV, yes, but not HCV,” said Strosberg. “With this study, there is now no good reason why researchers shouldn’t go after the HCV core protein.”
One of the problems in developing drugs for HCV is that it mutates at such prodigious rates; mutations in viral enzymes tend to lead to increased drug resistance.
By targeting the interactions of the core protein with itself and with other proteins, Strosberg and his colleagues have sought to reduce the problem of rapid mutation-because the core protein mutates much less than the other HCV proteins, and because mutations that affect the interface between core and itself or other proteins would be more likely to deactivate the virus anyway. Core proteins orchestrate the assembly and release of the infectious virus, as well as the disassembly of viral particles upon entering host cells.
Significantly, the new compounds not only inhibited dimerization of the core but also inhibited propagation of HCV in isolated hepatoma cells.