Details

Autor(en) / Beteiligte

• Althaus, Irene W
• Chou, James J
• Gonzales, Andrea J
• Deibel, Martin R
• Chou, Kuo Chen
• Kezdy, Ferenc J
• Romero, Donna L
• Palmer, John R
• Thomas, Richard C

Titel

Kinetic studies with the non-nucleoside HIV-1 reverse transcriptase inhibitor U-88204E

Ist Teil von

• Biochemistry (Easton), 1993-07, Vol.32 (26), p.6548-6554

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

1993

Quelle

MEDLINE

Beschreibungen/Notizen

• The bis(heteroaryl)piperazine U-88204E is a potent inhibitor of HIV-1 reverse transcriptase (RT) and possesses excellent anti-HIV activity in HIV-1-infected lymphocytes grown in tissue culture. Enzymatic kinetic studies of the RNA- and DNA-dependent DNA polymerases of RT were carried out in order to determine whether the inhibitor interacts directly with the template:primer or deoxyribonucleotide triphosphate (dNTP) binding sites of the polymerase. The experimental results were analyzed using steady-state or Briggs-Haldane kinetics, by assuming that the template:primer binds to the enzyme first followed by the dNTP and that the polymerase functions processively. The results of the analysis show that the inhibitor acts as a mixed to noncompetitive inhibitor with respect to both the template:primer and the dNTP binding sites. The potency of U-88204E on the RNA-directed DNA polymerase activity depends on the base composition of the template:primer. The Ki values for the poly(rC):(dG)10-directed reactions were at least 7 times lower than the ones for reactions directed by poly(rA):(dT)10. The inhibitor did not inhibit the RNase H function of HIV-1 RT nor did it impair the RNA-directed DNA polymerase activity of HIV-2 RT. These data thus demonstrate the unique specificity of U-88204E for HIV-1 RT.