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Advanced HIV Drug Approved for Resistant Infections
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.
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| Darunavir molecule bound to HIV protease. Image courtesy
of Dr. Arun K. Ghosh. |
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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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