Jefferson scientists show drug is effective against a Hepatitis C Virus model in the ...( appear extremely sensitive to thesed...)

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 n
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Contact: Steve Benowitz
steven.benowitz@mail.tju.edu
215-955-5291
Thomas Jefferson University
11-Oct-1999

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