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

doi:10.1128/AAC.01351-17

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

Center for Drug Design

Research output: Contribution to journal › Article › peer-review

19 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 language	English (US)
Journal	Antimicrobial agents and chemotherapy
Volume	61
Issue number	10
DOIs	https://doi.org/10.1128/AAC.01351-17
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610509

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Kirby, K. A., Myshakina, N. A., Christen, M. T., Chen, Y. L., Schmidt, H. A., Huber, A. D., Xi, Z., Kim, S., Rao, R. K., Kramer, S. T., Yang, Q., Singh, K., Parniak, M. A., Wang, Z., Ishima, R., & Sarafianos, S. G. (2017). A 2-hydroxyisoquinoline-1,3-dione active-site RNase H inhibitor binds in multiple modes to HIV-1 reverse transcriptase. Antimicrobial agents and chemotherapy, 61(10). https://doi.org/10.1128/AAC.01351-17

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 2017, 'A 2-hydroxyisoquinoline-1,3-dione active-site RNase H inhibitor binds in multiple modes to HIV-1 reverse transcriptase', Antimicrobial agents and chemotherapy, vol. 61, no. 10. https://doi.org/10.1128/AAC.01351-17

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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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AU - Chen, Yue Lei

AU - Schmidt, Hilary A.

AU - Huber, Andrew D.

AU - Xi, Zhaoyong

AU - Kim, Seongmi

AU - Rao, Rohit K.

AU - Kramer, Skyler T.

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AU - Singh, Kamalendra

AU - Parniak, Michael A.

AU - Wang, Zhengqiang

AU - Ishima, Rieko

AU - Sarafianos, Stefan G.

N1 - 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.

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N2 - 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.

AB - 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.

KW - Human immunodeficiency virus

KW - Inhibitor

KW - RNase H

KW - Reverse transcriptase

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

Abstract

Bibliographical note

Keywords

UN SDGs

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