- WASHINGTON (Reuters) - Scientists said Thursday they had been able to "see"
the changes that allow the AIDS virus become resistant to drugs and hope
their images can help drug companies develop better ways to attack the
virus.
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- Stephen Harrison and colleagues at the
Howard Hughes Medical Institute at Harvard University were able to crystalize
and make an image of the reverse transcriptase enzyme that HIV uses to
replicate itself.
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- They caught the virus just after it attacked
a cell and used an instrument known as a synchrotron, which is a high-intensity,
high-energy X-ray crystallography machine, to record an image of the scene.
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- Reverse transcriptase is targeted by
five HIV drugs now on the market, from the original drug, Glaxo-Wellcome's
AZT, to Bristol-Myers Squibb's Videx.
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- They work by mimicking nucleotides, natural
building blocks of DNA in the cell. These nucleotides are used by the HIV
virus as it attacks a cell and injects its own genetic material into it,
thus forcing the cell to pump out copies of virus instead of dividing naturally.
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- Such an approach has worked fairly well.
Combined with drugs that attack the virus at a different stage of its cycle,
known as protease inhibitors, the drugs can suppress the viral infection
in many patients.
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- There is also a class of drugs known
as non-nucleoside reverse transcriptase inhibitors (NNRTIs), which also
affect reverse transcriptase but in different ways from the nucleoside
mimickers, known formally as nucleoside-analog reverse transcriptase inhibitors.
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- But HIV eventually mutates in many people
and becomes resistant to drugs.
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- Drug researchers have found that seeing
the physical structure of drugs and their biological targets can help them
design compounds that will work together. Many fit together physically,
like a lock and key.
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- Harrison's team confirmed that the virus
mutates in specific ways that allow it to, in effect, ignore the drugs.
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- "The clustering of the mutations
correlates with the chemical structure of the drug," they wrote in
a report in the journal Science.
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- The X-ray crystalography technique helped
them to see the physical structures. "It allows you to see every amino
acid, indeed every protein, in an atom," Harrison said in a telephone
interview.
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- Other scientists have found that the
reverse transcriptase enzyme of HIV has parts, or domains, referred to
as "fingers," "palm," "thumb" and "connection."
These are used by the enzyme to seize hold of the nucleoside much in the
way a human hand grasps something.
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- "If you hold your hand out with
the palm cupped, that's a crude description of the overall shape of the
protein," Harrison said.
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- The HIV reverse transcriptase enzyme
uses one particular nucleotide to copy its genetic material and start the
victim cell down the road to becoming a miniature virus factory. "We've
captured this enzyme in the act of copying a viral gene," Harrison
said.
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- As it does this, the "fingers"
curl in toward the "palm." Not only could Harrison's team see
this process, they could see the changes in the amino acids that make up
the protein that confer resistance to each drug.
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- "It allows us to understand and
rationalize the resistance," he said. "A major and annoying puzzle
had been ... that we had been unable to understand why those particular
mutations had conferred resistance."
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- Now that they understand, he said, perhaps
better drugs could be designed, and existing drugs could be used more effectively.
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