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

The ribonuclease 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 (IC₅₀ = 2.6 μM) and RNH functions (IC₅₀ = 0.65 μM) of RT, but is more effective against RNH. X-ray crystallography, NMR, and molecular modeling were used to show that YLC2-155 binds at the RNH active site in multiple conformations.

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