September 1, 2006

Advanced HIV Drug Approved for Resistant Infections

Darunavir molecule bound to HIV protease Darunavir molecule bound to HIV protease.Dr. Arun K. Ghosh. Credit: University of Colorado at Boulder, Office of News Services

For years, the human immunodeficiency virus (HIV), the virus that causes AIDS, has frustrated drug developers. The virus rapidly mutates and, as parts of its structure change, it becomes resistant to treatment. But doctors will soon have a potent new tool in their arsenal. The U.S. Food and Drug Administration recently approved Prezista (darunavir), the first antiviral drug designed to treat drug-resistant strains of HIV.

The new drug works by attaching to an HIV enzyme called protease, which the virus needs in order to reproduce properly, so that the virus can no longer use it. Eight such "protease inhibitors" are currently on the market and have greatly improved the quality of life for those suffering from HIV. However, these lose their effectiveness over time, often cause severe side effects and are ineffective against drug-resistant HIV strains.

Dr. Arun Ghosh, an organic chemist supported primarily by NIH's National Institute of General Medical Sciences, set out to create a molecule that would interact with a part of the virus that does not change as the virus evolves. Such a design would reduce the likelihood that the virus could become resistant to the new drug. Based on the structure of HIV protease when it is bound to inhibitors, he designed and synthesized a molecule that attaches to the protease “backbone,” a region that changes little.

The new drug Ghosh designed has fewer side effects than existing protease inhibitors because the dose required is significantly less. The molecule is smaller, more easily absorbed and better tolerated by the body. The FDA recently approved a pill-based therapy, and it's expected to be available to physicians this year.

Ghosh, now at Purdue University, continues to expand on the design, making alterations to the original molecule. "The most recent protease inhibitors we created are exceedingly potent," he said. The design, synthesis and evaluation of these new prototype protease inhibitors are detailed in a paper in the Aug. 24 issue of the Journal of Medicinal Chemistry. Their clinical development, however, is still some years away.

Ghosh said he hopes this structural design approach to combating drug-resistance could be applied to other viruses as well. He is currently involved in research into the SARS virus. — adapted from a story by Elizabeth K. Gardner of the Purdue News Service.

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