A 2-hydroxyisoquinoline-1,3-dione active site RNase H inhibitor binds in multiple modes to HIV-1 reverse transcriptase.

The RNase H (RNH) function of HIV -1 reverse transcriptase (RT) plays an essential part in the viral life cycle. We report the characterization of YLC2-155, a 2-hydroxyisoquinoline-1,3-dione (HID) -based active -site RNH inhibitor. YLC2-155 inhibits both polymerase (50% inhibitory concentration [IC50] 2.6 mu M) and RNH functions (IC50 = 0.65 mu M) of RT but is more effective against RNH. X-ray crystallography, nuclear magnetic resonance (NMR) analysis, and molecular modeling were used to show that YLC2-155 binds at the RNH-active site in multiple conformations.