Antiviral Advance: Drug disables enzyme from hepatitis C virus
John Travis
It's odd to think that anyone would look upon a person infected with the AIDS virus with even a tinge of envy, but some of the estimated 170 million people worldwide infected with hepatitis C virus (HCV) may do just that. Whereas AIDS researchers have developed powerful drugs, including protease inhibitors, that target specific HIV proteins, physicians typically treat HCV with less effective, general antiviral medications, such as interferon and ribavirin.
At least three drug companies have now identified compounds that inactivate a key HCV protease in cell cultures and animals. As reported in an upcoming Nature, one of the protease inhibitors has even slowed HCV replication in people, without any obvious side effects. That human trial was only a few days long, however, and questions remain about whether the particular protease inhibitor tested is safe for long-term use.
The potential new HCV drugs all bind to the viral protease known as nonstructural protein 3 (NS3). In order for HCV to reproduce, NS3 must split large viral proteins into smaller, functional fragments, says Paul C. Anderson of the drug company Boehringer Ingelheim in Laval, Quebec. The same protease may also interfere with the body's ability to respond to interferon, a compound that normally stimulates the immune system. As a result, NS3 may enable the virus to hide out in the body for years, while slowly causing liver damage.
Researchers at Boehringer Ingelheim recently designed an oral drug that inhibits NS3. The compound, known as BILN 2061, sailed through initial tests in cells and animals. When given twice a day for 2 days to volunteers infected with HCV but still healthy, the compound dramatically reduced the presence of the virus in the volunteers' bloodstreams, Anderson and his colleagues will report in Nature. At scientific meetings, the company has reported similar results in infected people with liver damage.
Despite this success, Boehringer Ingelheim hasn't yet committed to larger trials of BILN 2061. Anderson acknowledges that the drug has caused some heart damage in monkeys when given to them at high doses over long periods. Even so, he stresses, "we have not dropped this compound." The company is now consulting with outside experts about how to proceed with further testing of BILN 2061.
At a liver-disease meeting in Boston this week, scientists from two other drug companies described initial cell and animal tests of their own NS3 inhibitors. One of the firms, Vertex Pharmaceuticals in Cambridge, Mass., plans to begin testing its drug candidate in people early next year, according to a spokesperson.
"I think targeted therapy will work," says HCV researcher T. Jake Liang of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md. "I'm certainly optimistic we will have something in 5 years."
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References:
Lamarre, D., P.C. Anderson, et al. In press. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature. Abstract available at http://dx.doi.org/10.1038/nature02099.
Lin, K., et al. VX-950: A tight-binding HCV protease inhibitor with a superior sustained inhibitory response in HCV replicon cells. American Association for the Study of Liver Diseases 2003 Conference. Oct. 24–28. Boston. Abstract.
Further Readings:
2003. Vertex researchers report data on HCV protease inhibitor VX-950. Vertex Pharmaceuticals press release. Oct. 27. Available at http://www.natap.org/2003/AASLD/day2_2.htm.
Foy, E., et al. 2003. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300(May 16):1145–1148. Abstract available at http://dx.doi.org/10.1126/science.1082604.
Sources:
Paul C. Anderson
Department of Chemistry
Boehringer Ingelheim Ltd.
Laval, QC H7S 2G5
Canada
T. Jake Liang
Digestive Diseases Branch
NIDDK, National Institutes of Health
Building 10-9, Room B-16
Bethesda, MD 20892-1800
From Science News, Volume 164, No. 18, November 1, 2003, p. 276.
