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GlaxoSmithKline Drug Discovery and Development Award 2002

in the pipeline are integrase inhibitors, which interfere with the enzyme that binds the virus's newly created DNA to the host cell's DNA. Unlike the other two HIV enzymes, protease and reverse transcriptase for which quite a few drugs already exist there are no FDA-approved drugs targeting integrase. Integrase appears to be unique to HIV, which makes it a good target because a drug that interferes with it may not be very toxic to the person taking it.

History has shown, however, that within a year or two of patients' taking new drugs, HIV will undoubtedly mutate, leading to resistance. Therefore, researchers are trying to stay one step ahead and develop second- and third-generation integrase inhibitors. But in order to do that, it must be determined where the integrase inhibitors bind at the molecular level. That is the job undertaken by Nouri Neamati, Ph.D., for which GSK has awarded him $100,000. Dr. Neamati is studying an integrase inhibitor currently in human trials.

"Several groups have been working for 10 years to determine the full length crystal structure of integrase, which has proved difficult," said Dr. Neamati, assistant professor of pharmaceutical sciences at the University of Southern California School of Pharmacy. "Once the three-dimensional structure of integrase is solved and once we know to which amino acid drugs currently being study bind, we can develop second- and third-generation drugs."

Making Current Drugs More Effective

Once HIV fuses to a host cell, it is the job of the enzyme reverse transcriptase to copy the virus's RNA into DNA. Among the more than a dozen approved HIV/AIDS drugs are two reverse nucleoside transcriptase inhibitors (NRTIs) known as purine nucleoside analogs. Although they are effective in fighting the virus, the purine NRTIs have a major flaw: the chemical linkage between their two molecular parts, a sugar analog and a purine base, is unstable and therefore susceptible to being
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Contact: Elaine Salewske
esalewske@pcipr.com
312-558-1770
Public Communications Inc.
1-Oct-2002


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