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PDBsum entry 1dmp
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Aspartyl proteinase
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PDB id
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1dmp
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, Potency, Resistance profile, Human pharmacokinetics and X-Ray crystal structure of dmp 450.
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Authors
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C.N.Hodge,
P.E.Aldrich,
L.T.Bacheler,
C.H.Chang,
C.J.Eyermann,
S.Garber,
M.Grubb,
D.A.Jackson,
P.K.Jadhav,
B.Korant,
P.Y.Lam,
M.B.Maurin,
J.L.Meek,
M.J.Otto,
M.M.Rayner,
C.Reid,
T.R.Sharpe,
L.Shum,
D.L.Winslow,
S.Erickson-Viitanen.
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Ref.
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Chem Biol, 1996,
3,
301-314.
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PubMed id
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Abstract
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BACKGROUND: Effective HIV protease inhibitors must combine potency towards
wild-type and mutant variants of HIV with oral bioavailability such that drug
levels in relevant tissues continuously exceed that required for inhibition of
virus replication. Computer-aided design led to the discovery of cyclic urea
inhibitors of the HIV protease. We set out to improve the physical properties
and oral bioavailability of these compounds. RESULTS: We have synthesized DMP
450 (bis-methanesulfonic acid salt), a water-soluble cyclic urea compound and a
potent inhibitor of HIV replication in cell culture that also inhibits variants
of HIV with single amino acid substitutions in the protease. DMP 450 is highly
selective for HIV protease, consistent with displacement of the
retrovirus-specific structural water molecule. Single doses of 10 mg kg-1 DMP
450 result in plasma levels in man in excess of that required to inhibit
wild-type and several mutant HIVs. A plasmid-based, in vivo assay model suggests
that maintenance of plasma levels of DMP 450 near the antiviral IC90 suppresses
HIV protease activity in the animal. We did identify mutants that are resistant
to DMP 450, however; multiple mutations within the protease gene caused a
significant reduction in the antiviral response. CONCLUSIONS: DMP 450 is a
significant advance within the cyclic urea class of HIV protease inhibitors due
to its exceptional oral bioavailability. The data presented here suggest that an
optimal cyclic urea will provide clinical benefit in treating AIDS if it
combines favorable pharmacokinetics with potent activity against not only single
mutants of HIV, but also multiply-mutant variants.
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