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

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

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

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Human immunodeficiency virus
Inhibitor
RNase H
Reverse transcriptase

Publisher link

10.1128/AAC.01351-17

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

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.",

keywords = "Human immunodeficiency virus, Inhibitor, RNase H, Reverse transcriptase",

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

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doi = "10.1128/AAC.01351-17",

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AU - Kirby, Karen A.

AU - Myshakina, Nataliya A.

AU - Christen, Martin T.

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.

AU - Yang, Qiongying

AU - Singh, Kamalendra

AU - Parniak, Michael A.

AU - Wang, Zhengqiang

AU - Ishima, Rieko

AU - Sarafianos, Stefan G.

PY - 2017

Y1 - 2017

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

UR - https://www.scopus.com/pages/publications/85029759593

UR - https://www.scopus.com/pages/publications/85029759593#tab=citedBy

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DO - 10.1128/AAC.01351-17

M3 - Article

C2 - 28760905

AN - SCOPUS:85029759593

SN - 0066-4804

VL - 61

JO - Antimicrobial agents and chemotherapy

JF - Antimicrobial agents and chemotherapy

IS - 10

ER -

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

Abstract

Bibliographical note

UN SDGs

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