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

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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
JournalAntimicrobial agents and chemotherapy
Volume61
Issue number10
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
This research was supported in part by the National Institutes of Health (grant AI100890 to S.G.S., M.A.P., and Z.W. and grant GM105401 to R.I.). The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under contract DE-AC02-05CH11231.

Publisher Copyright:
© 2017 American Society for Microbiology. All Rights Reserved.

Keywords

  • Human immunodeficiency virus
  • Inhibitor
  • RNase H
  • Reverse transcriptase

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