RT Journal Article
SR Electronic
T1 Metal-Dependent Inhibition of HIV-1 Integrase by β-Diketo Acids and Resistance of the Soluble Double-Mutant (F185K/C280S)
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 600
OP 609
DO 10.1124/mol.64.3.600
VO 64
IS 3
A1 Christophe Marchand
A1 Allison A. Johnson
A1 Rajeshri G. Karki
A1 Godwin C. G. Pais
A1 Xuechun Zhang
A1 Kiriana Cowansage
A1 Tapan A. Patel
A1 Marc C. Nicklaus
A1 Terrence R. Burke, Jr.
A1 Yves Pommier
YR 2003
UL http://molpharm.aspetjournals.org/content/64/3/600.abstract
AB The β-diketo acids (DKAs) represent a major advance for anti–HIV-1 integrase drug development. We compared the inhibition of HIV-1 integrase by six DKA derivatives using the wild-type enzyme or the double-mutant F185K/C280S, which has been previously used for crystal structure determinations. With the wild-type enzyme, we found that DKAs could be classified into two groups: those similarly potent in the presence of magnesium and manganese and those potent in manganese and relatively ineffective in the presence of magnesium. Both the aromatic and the carboxylic or tetrazole functions of DKAs determined their metal selectivity. The F185K/C280S enzyme was markedly more active in the presence of manganese than magnesium. The F185K/C280S integrase was also relatively resistant to the same group of DKAs that were potent in the presence of magnesium with the wild-type enzyme. Resistance was caused by a synergistic effect from both the F185K and C280S mutations. Molecular modeling and docking suggested metal-dependent differences for binding of DKAs. Molecular modeling also indicated that the tetrazole or the azido groups of some derivatives could directly chelate magnesium or manganese in the integrase catalytic site. Together, these experiments suggest that DKAs recognize conformational differences between wild-type and the double-mutant HIV-1 integrase, because they chelate the magnesium or manganese in the enzyme active site and compete for DNA binding.