Glucosidase inhibitors may have a future as broad-based hepatitis drugs Researchers at Jefferson Medical College may have found a promising drug against the hepatitis C virus (HCV). While they are quick to point out that the drug, N-nonyl-DNJ, stopped only a surrogate virus - and not the actual HCV - from reproducing in the laboratory, they believe the findings, which build on their earlier success against hepatitis B virus (HBV), may someday lead to a single drug against both viruses.
Timothy Block, Ph.D., professor of biochemistry and molecular pharmacology and medicine at Thomas Jefferson University in Philadelphia, and colleagues at Oxford University in Oxford, UK, used the drug to inhibit the activity of an important cellular enzyme, glucosidase. This in turn prevented the bovine diarrhea virus, BVDV, which is a tissue culture model of HCV, from making more virus. Dr. Block believes this class of drugs, called glucosidase inhibitors, "have a reasonable likelihood of working against HCV therapeutically." Because HCV cannot be grown in the lab, researchers use BVDV as a testing model.
"This is the first drug since alpha-interferon to my knowledge for which there is published experimental evidence against HCV - in the form of BVDV susceptibility," says Dr. Block, who is a member of Jefferson's Kimmel Cancer Center and director of the Jefferson Center for Biomedical Research and Agricultural Medicine.
The drug may sidestep resistant viruses, the bane of current anti-hepatitis treatments. "Since the drugs target a host cellular enzyme at very non-toxic doses, rather than the virus, we think that resistance to the drugs will not be a problem,"he says.
The findings appear Oct. 12 in the Proceedings of the National Academy of Sciences. Viruses such as HCV, HBV and BVDV reproduce by actually "budding out from intracellular membranes." The viruses appear "extremely sensitive to these drugs under conditions where the normal cellular processes are not affected," Dr. Block explains. "Because we target this cell pathway upon which a family of viruses is dependent as our target gives us an opportunity to develop drugs that have broad activity."
The next step, Dr. Block says, is to experimentally test the drug against HCV and to determine why the virus is so sensitive. Dr. Block and in his colleagues, in conjunction with Synergy, a biotechnology company located in Edison, NJ, would like to also develop improved versions of nonyl-DNJ. Jefferson and Oxford University previously licensed drug development rights to Monsanto-Searle, which in turn created Synergy.
"HCV represents an important unmet medical need," Dr. Block says. In earlier work, and Dr. Block and his colleagues at several institutions found that N-nonyl-DNJ interfered with a specific step in the life cycle of the woodchuck hepatitis virus, which is an animal model for HBV, essentially shutting down its ability to infect a cell. As a result, levels of the virus in the animals' bloodstream drop dramatically. They found that a very specific step in the life cycle of the virus that can be selectively inhibited by N-nonyl-DNJ. They discovered that the drug worked by inhibiting the first step in the glycosylation process that all cell glycoproteins go through to reproduce and be able to infect. The host cellular glycoproteins appear to be far less sensitive to this inhibition than is HBV.
BVDV and HCV are viruses composed of RNA, as opposed to HBV, which is a made up of DNA. "They have different genomes but similar methods of envelope development - budding from the endoplasmic reticulum (ER)," Dr. Block says. "We think they will all be very sensitive to N-nonyl-DNJ, since this drug blocks the first step in ER glycoprocessing which is needed for some but not all proteins to fold in the ER." In both HBV and now HCV, the researchers were able to block the creation of a virus "envelope," locking the virus within the infected cell. The virus, then, is rendered "dead," or non-infectious.
Acccording to Dr. Block, worldwide, HCV chronically infects some 100 million people, with as many as four million chronic carriers in the United States. Those at risk for contracting HCV include intravenous drug abusers and anyone who had transfusions prior to 1990, when blood supply screening for HCV began. Together, HBV and HCV chronically infect more than 400 million people in the world. Approximately one million people die each year from HBV- and HCV-related liver diseases, such as hepatitis, cirrhosis and cancer.
Scientists from several other institutions participated in the study, such as Nicole Zitzmann, Ph.D., Raymond Dwek, D. Phil., FRSC, Oxford University, and Nobel laureate Baruch Blumberg, M.D., Ph.D., Fox Chase Cancer Center.
Journal
Proceedings of the National Academy of Sciences