1dmp
From Proteopedia
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STRUCTURE OF HIV-1 PROTEASE COMPLEX
Overview
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.
About this Structure
1DMP is a Single protein structure of sequence from Human immunodeficiency virus 1 with DMQ as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 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
Page seeded by OCA on Thu Nov 8 13:58:48 2007
