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A 2-Hydroxyisoquinoline-1,3-Dione Active-Site RNase H Inhibitor Binds in Multiple Modes to HIV-1 Reverse Transcriptase.

A 2-Hydroxyisoquinoline-1,3-Dione Active-Site RNase H Inhibitor Binds in Multiple Modes to HIV-1 Reverse Transcriptase.
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Kirby KA, Myshakina NA, Christen MT, Chen YL, Schmidt HA, Huber AD, Xi Z, Kim S, Rao RK, Kramer ST, Yang Q, Singh K, Parniak MA, Wang Z, Ishima R, Sarafianos SG,


Kirby KA, Myshakina NA, Christen MT, Chen YL, Schmidt HA, Huber AD, Xi Z, Kim S, Rao RK, Kramer ST, Yang Q, Singh K, Parniak MA, Wang Z, Ishima R, Sarafianos SG, (click to view)

Kirby KA, Myshakina NA, Christen MT, Chen YL, Schmidt HA, Huber AD, Xi Z, Kim S, Rao RK, Kramer ST, Yang Q, Singh K, Parniak MA, Wang Z, Ishima R, Sarafianos SG,

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Antimicrobial agents and chemotherapy 2017 09 2261(10) pii 10.1128/AAC.01351-17

Abstract

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 μM) and RNH functions (IC50 = 0.65 μM) 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.

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