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Title
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Targeting HIV reverse transcriptase for anti-AIDS drug design: structural and biological considerations for chemotherapeutic strategies.
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Authors
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E.Arnold,
K.Das,
J.Ding,
P.N.Yadav,
Y.Hsiou,
P.L.Boyer,
S.H.Hughes.
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Ref.
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Drug Des Discov, 1996,
13,
29-47.
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PubMed id
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Abstract
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The reverse transcriptase of HIV is a key target for the antiviral treatment of
AIDS. Numerous potent inhibitors of RT have been described including all of the
drugs that have been currently licensed for the treatment of AIDS, but their
efficacy has been limited by the emergence of drug-resistant HIV variants.
Extensive biochemical, genetic, and clinical data about HIV RT enzymatic
mechanisms, inhibition, and drug resistance have been reported. This
information, taken together with structural data from crystallographic studies
of HIV-1 RT, has set the stage for structure-based design of improved inhibitors
of this essential viral enzyme. Comparisons of the different crystal structures
of HIV-1 RT shows that the enzyme has great conformational flexibility,
providing additional possibilities for drug targeting. Recent clinical and
virological data suggest that HIV-1 RT enzymes that carry drug-resistance
mutations can be substantially impaired and that combinations of RT inhibitors
can produce significant clinical benefit in the treatment of AIDS. An immediate
goal is to use the available information to design specific inhibitors or
combination therapies that will select for relatively less fit HIV variants.
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