Two compounds that act on novel binding sites for HIV protease--an enzyme critical to the life cycle of the virus that causes AIDS--have been identified by researchers at the Scripps Research Institute and collaborating institutions, including Pfizer and GlaxoSmithKline. The discovery lays the foundation for the development of a new class of anti-HIV drugs to enhance existing therapies, treat drug-resistant strains of the disease, and slow the evolution of drug resistance in the virus. Drugs that block the HIV protease already exist and currently make up an important part of the successful AIDS drug cocktail known as highly active anti-retroviral therapy (HAART). Compared with the nine U.S. Food and Drug Administration (FDA)-approved drugs that target HIV protease, however, the two new compounds, which are small chemical units or "fragments," bind with two novel parts of the molecule. This could make future drugs incorporating the fragments' novel structural elements a useful complement to existing treatments. "The study's results open the door to a whole new approach to drug design against HIV protease," said Scripps Research Associate Professor C. David Stout, senior author of the study. "The fragments bound at not one, but two, different crevices in protease outside the active site. This is an important proof-of-concept that the protease molecule has two non-active site binding pockets (allosteric sites) which can now be exploited as a powerful new strategy to combat drug-resistance in HIV." The article describing this work is currently available online and will be featured as the cover story of the March issue of Chemical Biology & Drug Design. [Press release]
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