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Preferential Inhibition of the Magnesium-Dependent Strand Transfer Reaction of HIV-1 Integrase by -Hydroxytropolones

Laboratory of Molecular Pharmacology (E.A.S., A.A.J., C.M.) and HIV and AIDS Malignancy Branch (D.A.D., R.Y.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Integration is a crucial step in the life cycle of human immunodeficiency virus type 1 (HIV-1); therefore, inhibitors of HIV-1 integrase are candidates for antiretroviral therapy. Two 7-hydroxytropolone derivatives (-hydroxytropolones) were found to inhibit HIV-1 integrase. A structure-activity relationship investigation with several tropolone derivatives from The National Cancer Institute compound repository demonstrated that the 7-hydroxy group is essential for integrase inhibition. -Hydroxytropolones preferentially inhibit strand transfer and are inhibitory both in the presence of magnesium or manganese. Lack of inhibition of disintegration in the presence of magnesium coupled with results from different cross-linking assays suggests -hydroxytropolones as interfacial inhibitors. We propose that -hydroxytropolones chelate the divalent metal (Mg²⁺ or Mn²⁺) in the enzyme active site. The most active compound against HIV-1 integrase in biochemical assays [2,4,6-cycloheptatrien-1-one, 2,7-dihydroxy-4-isopropyl (NSC 18806) IC₅₀ = 4.8 ± 2.5 µM] exhibits weak cytoprotective activity against HIV-1_IIIB in a cell-based assay. -Hydroxytropolones represent a new family of inhibitors for the development of novel drugs against HIV infection.

Address correspondence to: Dr. Yves Pommier, Laboratory of Molecular Pharmacology, Bldg. 37, Room 5068, National Institutes of Health, Bethesda, MD 20892. E-mail: pommier{at}nih.gov

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