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1dmp

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{{STRUCTURE_1dmp| PDB=1dmp | SCENE= }}
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'''STRUCTURE OF HIV-1 PROTEASE COMPLEX'''
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===STRUCTURE OF HIV-1 PROTEASE COMPLEX===
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==Overview==
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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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(as it appears on PubMed at http://www.pubmed.gov), where 8807858 is the PubMed ID number.
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{{ABSTRACT_PUBMED_8807858}}
==About this Structure==
==About this Structure==
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[[Category: Polyprotein]]
[[Category: Polyprotein]]
[[Category: Rna-directed dna polymerase]]
[[Category: Rna-directed dna polymerase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 14:01:52 2008''
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Revision as of 20:18, 30 June 2008

Image:1dmp.png

Template:STRUCTURE 1dmp

STRUCTURE OF HIV-1 PROTEASE COMPLEX

Template:ABSTRACT PUBMED 8807858

About this Structure

1DMP is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.

Reference

Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450., Hodge CN, Aldrich PE, Bacheler LT, Chang CH, Eyermann CJ, Garber S, Grubb M, Jackson DA, Jadhav PK, Korant B, Lam PY, Maurin MB, Meek JL, Otto MJ, Rayner MM, Reid C, Sharpe TR, Shum L, Winslow DL, Erickson-Viitanen S, Chem Biol. 1996 Apr;3(4):301-14. PMID:8807858

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