3-hydroxypyrimidine-2,4-diones as novel hepatitis b virus antivirals targeting the viral ribonuclease H

Andrew D. Huber; Eleftherios Michailidis; Jing Tang; Maritza N. Puray-Chavez; Maria Boftsi; Jennifer J. Wolf; Kelsey N. Boschert; Megan A. Sheridan; Maxwell D. Leslie; Karen A. Kirby; Kamalendra Singh; Hiroaki Mitsuya; Michael A. Parniak; Zhengqiang Wang; Stefan G. Sarafianos

doi:10.1128/AAC.00245-17

3-hydroxypyrimidine-2,4-diones as novel hepatitis b virus antivirals targeting the viral ribonuclease H

Andrew D. Huber, Eleftherios Michailidis, Jing Tang, Maritza N. Puray-Chavez, Maria Boftsi, Jennifer J. Wolf, Kelsey N. Boschert, Megan A. Sheridan, Maxwell D. Leslie, Karen A. Kirby, Kamalendra Singh, Hiroaki Mitsuya, Michael A. Parniak, Zhengqiang Wang, Stefan G. Sarafianos

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

21 Scopus citations

Abstract

Hepatitis B virus (HBV) RNase H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help to more effectively control HBV infections. Here, we report 3-hydroxypyrimidine-2,4- diones as novel HBV RNHIs with antiviral activity. We synthesized and tested 52 analogs and found 4 that inhibit HBV RNH activity in infected cells. Importantly, 2 of these compounds inhibited HBV replication in the low micromolar range.

Original language	English (US)
Article number	e00245-17
Journal	Antimicrobial agents and chemotherapy
Volume	61
Issue number	6
DOIs	https://doi.org/10.1128/AAC.00245-17
State	Published - Jun 2017

Bibliographical note

Funding Information:
This work was supported in part by grants from the National Institutes of Health (NIH) (AI100890 and AI121315 to S.G.S. and Z.W.) and Trail to a Cure. A.D.H. is supported by NIH grant AI100890-S1, M.N.P.-C. is supported by the Fulbright Student Program, and J.J.W. is supported by a Life Sciences Fellowship from the University of Missouri. We also acknowledge partial support from Kumamoto University and the Japan Agency for Medical Research and Development.

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

Keywords

Antiviral agents
Hepatitis B virus
Rnase H

UN SDGs

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

Publisher link

10.1128/AAC.00245-17

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444124

Find It

Find It at U of M Libraries

Cite this

Huber, A. D., Michailidis, E., Tang, J., Puray-Chavez, M. N., Boftsi, M., Wolf, J. J., Boschert, K. N., Sheridan, M. A., Leslie, M. D., Kirby, K. A., Singh, K., Mitsuya, H., Parniak, M. A., Wang, Z., & Sarafianos, S. G. (2017). 3-hydroxypyrimidine-2,4-diones as novel hepatitis b virus antivirals targeting the viral ribonuclease H. Antimicrobial agents and chemotherapy, 61(6), Article e00245-17. https://doi.org/10.1128/AAC.00245-17

Huber, AD, Michailidis, E, Tang, J, Puray-Chavez, MN, Boftsi, M, Wolf, JJ, Boschert, KN, Sheridan, MA, Leslie, MD, Kirby, KA, Singh, K, Mitsuya, H, Parniak, MA, Wang, Z & Sarafianos, SG 2017, '3-hydroxypyrimidine-2,4-diones as novel hepatitis b virus antivirals targeting the viral ribonuclease H', Antimicrobial agents and chemotherapy, vol. 61, no. 6, e00245-17. https://doi.org/10.1128/AAC.00245-17

@article{d5f12d018f224a318b27fd4189cba301,

title = "3-hydroxypyrimidine-2,4-diones as novel hepatitis b virus antivirals targeting the viral ribonuclease H",

abstract = "Hepatitis B virus (HBV) RNase H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help to more effectively control HBV infections. Here, we report 3-hydroxypyrimidine-2,4- diones as novel HBV RNHIs with antiviral activity. We synthesized and tested 52 analogs and found 4 that inhibit HBV RNH activity in infected cells. Importantly, 2 of these compounds inhibited HBV replication in the low micromolar range.",

keywords = "Antiviral agents, Hepatitis B virus, Rnase H",

author = "Huber, {Andrew D.} and Eleftherios Michailidis and Jing Tang and Puray-Chavez, {Maritza N.} and Maria Boftsi and Wolf, {Jennifer J.} and Boschert, {Kelsey N.} and Sheridan, {Megan A.} and Leslie, {Maxwell D.} and Kirby, {Karen A.} and Kamalendra Singh and Hiroaki Mitsuya and Parniak, {Michael A.} and Zhengqiang Wang and Sarafianos, {Stefan G.}",

note = "Funding Information: This work was supported in part by grants from the National Institutes of Health (NIH) (AI100890 and AI121315 to S.G.S. and Z.W.) and Trail to a Cure. A.D.H. is supported by NIH grant AI100890-S1, M.N.P.-C. is supported by the Fulbright Student Program, and J.J.W. is supported by a Life Sciences Fellowship from the University of Missouri. We also acknowledge partial support from Kumamoto University and the Japan Agency for Medical Research and Development. Publisher Copyright: {\textcopyright} 2017 American Society for Microbiology. All Rights Reserved.",

year = "2017",

month = jun,

doi = "10.1128/AAC.00245-17",

language = "English (US)",

volume = "61",

journal = "Antimicrobial agents and chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

number = "6",

}

TY - JOUR

T1 - 3-hydroxypyrimidine-2,4-diones as novel hepatitis b virus antivirals targeting the viral ribonuclease H

AU - Huber, Andrew D.

AU - Michailidis, Eleftherios

AU - Tang, Jing

AU - Puray-Chavez, Maritza N.

AU - Boftsi, Maria

AU - Wolf, Jennifer J.

AU - Boschert, Kelsey N.

AU - Sheridan, Megan A.

AU - Leslie, Maxwell D.

AU - Kirby, Karen A.

AU - Singh, Kamalendra

AU - Mitsuya, Hiroaki

AU - Parniak, Michael A.

AU - Wang, Zhengqiang

AU - Sarafianos, Stefan G.

N1 - Funding Information: This work was supported in part by grants from the National Institutes of Health (NIH) (AI100890 and AI121315 to S.G.S. and Z.W.) and Trail to a Cure. A.D.H. is supported by NIH grant AI100890-S1, M.N.P.-C. is supported by the Fulbright Student Program, and J.J.W. is supported by a Life Sciences Fellowship from the University of Missouri. We also acknowledge partial support from Kumamoto University and the Japan Agency for Medical Research and Development. Publisher Copyright: © 2017 American Society for Microbiology. All Rights Reserved.

PY - 2017/6

Y1 - 2017/6

N2 - Hepatitis B virus (HBV) RNase H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help to more effectively control HBV infections. Here, we report 3-hydroxypyrimidine-2,4- diones as novel HBV RNHIs with antiviral activity. We synthesized and tested 52 analogs and found 4 that inhibit HBV RNH activity in infected cells. Importantly, 2 of these compounds inhibited HBV replication in the low micromolar range.

AB - Hepatitis B virus (HBV) RNase H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help to more effectively control HBV infections. Here, we report 3-hydroxypyrimidine-2,4- diones as novel HBV RNHIs with antiviral activity. We synthesized and tested 52 analogs and found 4 that inhibit HBV RNH activity in infected cells. Importantly, 2 of these compounds inhibited HBV replication in the low micromolar range.

KW - Antiviral agents

KW - Hepatitis B virus

KW - Rnase H

UR - http://www.scopus.com/inward/record.url?scp=85019681004&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019681004&partnerID=8YFLogxK

U2 - 10.1128/AAC.00245-17

DO - 10.1128/AAC.00245-17

M3 - Article

C2 - 28320718

AN - SCOPUS:85019681004

SN - 0066-4804

VL - 61

JO - Antimicrobial agents and chemotherapy

JF - Antimicrobial agents and chemotherapy

IS - 6

M1 - e00245-17

ER -

3-hydroxypyrimidine-2,4-diones as novel hepatitis b virus antivirals targeting the viral ribonuclease H

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this