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

Karen A. Kirby | Zendy; Nataliya Myshakina | Zendy; Martin T. Christen | Zendy; Yue-Lei Chen | Zendy; Hilary A. Schmidt | Zendy; Andrew D. Huber | Zendy; Zhaoyong Xi | Zendy; Seongmi Kim | Zendy; Rohit Rao | Zendy; Skyler T. Kramer | Zendy; Qiongying Yang | Zendy; Kamalendra Singh | Zendy; Michael A. Parniak | Zendy; Zhengqiang Wang | Zendy; Rieko Ishima | Zendy; Stefan G. Sarafianos | Zendy

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

Author(s) -

Karen A. Kirby,

Nataliya Myshakina,

Martin T. Christen,

Yue-Lei Chen,

Hilary A. Schmidt,

Andrew D. Huber,

Zhaoyong Xi,

Seongmi Kim,

Rohit Rao,

Skyler T. Kramer,

Qiongying Yang,

Kamalendra Singh,

Michael A. Parniak,

Zhengqiang Wang,

Rieko Ishima,

Stefan G. Sarafianos

Publication year - 2017

Publication title -

antimicrobial agents and chemotherapy

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.07

H-Index - 259

eISSN - 1070-6283

pISSN - 0066-4804

DOI - 10.1128/aac.01351-17

Subject(s) - reverse transcriptase , rnase h , active site , ic50 , microbiology and biotechnology , stereochemistry , human immunodeficiency virus (hiv) , binding site , rnase p , chemistry , enzyme , polymerase , biology , virology , biochemistry , in vitro , rna , gene

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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