       Document 0982
 DOCN  M9620982
 TI    Effects of tyrphostins, protein kinase inhibitors, on human
       immunodeficiency virus type 1 integrase.
 DT    9602
 AU    Mazumder A; Gazit A; Levitzki A; Nicklaus M; Yung J; Kohlhagen G;
       Pommier Y; Laboratories of Molecular Pharmacology and Medicinal
       Chemistry,; National Cancer Institute, Bethesda, Maryland 20892, USA.
 SO    Biochemistry. 1995 Nov 21;34(46):15111-22. Unique Identifier : AIDSLINE
       MED/96072749
 AB    Efficient replication of HIV-1 requires establishment of the proviral
       state, i.e., the integration of a DNA copy of the viral genome,
       synthesized by reverse transcriptase, into a chromosome of the host
       cell. Integration is catalyzed by the viral integrase protein. We have
       previously reported that phenolic moieties in compounds such as
       napthoquinones, flavones, caffeic acid phenethyl ester (CAPE), and
       curcumin confer inhibitory activity against HIV-1 integrase. We have
       extended these findings by examining the effects of tryphostins,
       tyrosine kinase inhibitors. The catalytic activities of HIV-1 integrase
       and the formation of enzyme-DNA complexes using photocross-linking were
       examined. Both steps of the integration reaction, 3'-processing and
       strand transfer, were inhibited by tyrphostins at micromolar
       concentrations. The DNA binding activity of integrase was inhibited at
       higher concentrations of tryphostins. Disintegration, an apparent
       reversal of the strand transfer reaction, catalyzed by an integrase
       mutant lacking the N-terminal zinc finger and C-terminal DNA binding
       domains is also inhibited by tyrphostins, indicating that the binding
       site for these compounds resides in the central catalytic core of HIV-1
       integrase. Binding of tyrphostins at or near the integrase catalytic
       site was also suggested by experiments showing a global inhibition of
       the choice of attacking nucleophile in the 3'-processing reaction. None
       of the tryphostins tested inhibited eukaryotic topoisomerase I, even at
       100 microM, suggesting selectivity for integrase inhibition.
       Molecular-modeling studies have revealed that, after energy
       minimization, several tyrphostins may adopt folded conformations. The
       similarity of the tyrphostin family to other families of inhibitors is
       discussed. Tyrphostins may provide lead compounds for development of
       novel antiviral agents for the treatment of acquired immunodeficiency
       syndrome based upon inhibition of HIV-1 integrase.
 DE    Antiviral Agents/*PHARMACOLOGY  Base Sequence  Binding Sites
       Cross-Linking Reagents  DNA/CHEMISTRY/METABOLISM  DNA
       Nucleotidyltransferases/*ANTAGONISTS & INHIB/METABOLISM  Enzyme
       Inhibitors/*PHARMACOLOGY  HIV-1/*ENZYMOLOGY  Molecular Sequence Data
       Nitriles/*PHARMACOLOGY  Protein-Tyrosine Kinase/*ANTAGONISTS & INHIB
       Support, U.S. Gov't, P.H.S.  Ultraviolet Rays  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

