RT Journal Article
SR Electronic
T1 Preferential Inhibition of the Magnesium-Dependent Strand Transfer Reaction of HIV-1 Integrase by α-Hydroxytropolones
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1454
OP 1460
DO 10.1124/mol.105.020321
VO 69
IS 4
A1 Elena A. Semenova
A1 Allison A. Johnson
A1 Christophe Marchand
A1 David A. Davis
A1 Robert Yarchoan
A1 Yves Pommier
YR 2006
UL http://molpharm.aspetjournals.org/content/69/4/1454.abstract
AB 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 (α-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. α-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 α-hydroxytropolones as interfacial inhibitors. We propose that α-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-1IIIB in a cell-based assay. α-Hydroxytropolones represent a new family of inhibitors for the development of novel drugs against HIV infection.