Document 0588
 DOCN  M9480588
 TI    Structure-based design of symmetric inhibitors of HIV-1 protease.
 DT    9410
 AU    Erickson J; Kempf D; Structural Biochemistry Program, Frederick
       Biomedical; Supercomputing Center, National Cancer Institute, Frederick;
       Cancer Research and Development Center, Maryland.
 SO    Arch Virol Suppl. 1994;9:19-29. Unique Identifier : AIDSLINE
       MED/94305396
 AB    HIV-1, the causative agent of AIDS, encodes a protease that processes
       the viral polyproteins into the structural proteins and replicative
       enzymes found in mature virions. Protease activity has been shown to be
       essential for the proper assembly and maturation of fully infectious
       HIV-1. Thus, the HIV-1 protease (HIV PR) has become an important target
       for the design of antiviral agents for AIDS. Analysis of the
       three-dimensional structures of related aspartic proteinases, and later
       of Rous sarcoma virus protease, indicated that the active site and
       extended substrate binding cleft exhibits two-fold (C2) symmetry at the
       atomic level. We therefore set out to test whether compounds that
       contained a C2 axis of symmetry, and that were structurally
       complementary to the active site region, could be potent and selective
       inhibitors of HIV PR. Two novel classes of C2 or pseudo-C2 symmetric
       inhibitors were designed, synthesized and shown to display potent
       inhibitory activity towards HIV PR, and one of these, A-77003, recently
       entered clinical trials. The structure of the complex with A-74704 was
       solved using X-ray crystallographic methods and revealed a highly
       symmetric mode of binding, confirming our initial design principles.
       These studies demonstrate that relatively simple symmetry considerations
       can give rise to novel compound designs, allowing access to imaginative
       new templates for synthesis that can be translated into experimental
       therapeutic agents.
 DE    *Drug Design  HIV Protease/*DRUG EFFECTS  HIV Protease
       Inhibitors/*PHARMACOLOGY  HIV-1/*DRUG EFFECTS/GROWTH & DEVELOPMENT
       Models, Molecular  Molecular Conformation  Structure-Activity
       Relationship  Sugar Alcohols/*CHEMISTRY  Valine/*ANALOGS &
       DERIVATIVES/CHEMISTRY  JOURNAL ARTICLE  REVIEW  REVIEW, TUTORIAL

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