With the ever-decreasing number of hepatitis B researchers, the Hepatitis B Foundation (HBF) decided to step in and reverse this alarming trend. In 2004, the HBF established the Institute for Hepatitis and Virus Research (IHVR), focused on hepatitis B and C, and liver cancer research (read B Informed, Winter, 2005 issue). A little more than one year later, the institute is making its research mark.

An 80,000-plus compound library serves as the linchpin of the research efforts at the institute, which is focused on two main areas: antiviral drug and biomarker discovery. The institute's high-throughput robotics system screens compounds efficiently for potential activity against a variety of diseases, including hepatitis B and C, and liver cancer. The proteomics laboratory and mass spectrometry facility provide IHVR scientists with up-to-date equipment.

"These high-tech resources have made IHVR a significant player in the nonprofit research world," said Timothy Block, Ph.D., professor and director of the Drexel University Institute for Biotechnology and Virology Research, and founding director of the IHVR.

Scientists such as Drug Discovery program Project Leader Andy Cuconati, Ph.D., have already filed provisional patents on several promising families of compounds that show activity against HBV.

Cuconati and his colleagues are looking for compounds as potential therapeutics against HBV. They have screened 80,000 individual organic molecules in the institute's compound library, using an experimental system that mimics a part of the virus's life cycle - specifically, the process by which viral particles leave infected liver cells and spread in the bloodstream. Preventing the process may be key to halting infection. The scientists used genetically engineered liver cancer cells that produce and secrete these particles in growth medium.

They initially found about 1,700 compounds that were active against HBV, though most of those were toxic. Eventually, they whittled the candidate list to 150. "We'll be characterizing these in the future and categorizing those that are most promising as inhibitors of HBV and which are most attractive for chemical modification and development into drugs," Cuconati explained.

The team is also screening the library for compounds that can remove the "stable DNA" of the HBV from inside infected liver cells. In those chronically infected with HBV, the viral DNA is stored in a different form in the nucleus of the infected cell. "One of the Holy Grails of HBV research is to find a compound to remove this persistent form of virus, one which can be modified into a drug," Cuconati said.

Senior scientist Ramila Philip, Ph.D., leads the Biomarker Discovery program. Philip, who also heads the IHVR proteomic facility, specializes in immunoproteomics, which entails studying specific proteins involved in immune response.

She and her research group are taking advantage of the IHVR's mass spectrometry facility in their search for protein biomarkers for liver cancer. They compare blood samples from liver cancer patients and healthy individuals, attempting to identify cancer proteins the patients' immune systems have generated antibody responses to. With the help of mass spectrometry and other techniques, they are hoping that these protein "antigens" will prove valuable in early detection of liver cancer. Such antigens, she noted, might be used in immune-based therapies.

They are also attempting to identify peptides (pieces of proteins) in HBV-infected cells treated with antiviral drugs, which affects the expression of viral proteins and the processing of peptides derived from viral proteins. Comparing antiviral-treated cells with untreated, HBV-infected cells can provide clues on how well a drug is working and its potential effect on additional immune-based therapies.

Kunwar Shailubhai, Ph.D., M.B.A., has high hopes for a program he is planning to spearhead in hepatocellular carcinoma, which can result from chronic HBV infection. He currently is studying an enzyme target that can be used against this primary liver cancer, trying to find specific molecules that can block the enzyme's activity. The enzyme, a member of a family of proteins known as kinases, plays vital roles in various cellular functions, including cell growth, and is one of the most widely chased drug targets in cancer drug development. Many such so-called "targeted therapies" are aimed at halting abnormal kinase activity - a key, it's hoped to arresting or even reversing cancer growth.

But finding such specific inhibitors is tricky. Shailubhai said that he and his co-workers know the basic chemical structure of the enzyme, and plan to search the IHVR's compound library for candidates, and then test them in the laboratory test tube. "The lead compounds would then be tested in mice and woodchucks," he noted, adding that woodchucks are natural carriers of HBV in the wild.

"Kinases are one of the hottest drug targets in oncology," Shailubhai said. "Finding compounds to block the kinase's activity could have applications in a number of other cancers, including lung and colon cancer."

For more information about the Institute for Hepatitis and Virus Research, visit www.ihvr.org.

BInformed, Fall 2005.