Selective inhibition of the West Nile virus methyltransferase by nucleoside analogs

Hui Chen; Lihui Liu; Susan A. Jones; Nilesh Banavali; Jorden Kass; Zhong Li; Jing Zhang; Laura D. Kramer; Arun K. Ghosh; Hongmin Li

doi:10.1016/j.antiviral.2012.12.012

Selective inhibition of the West Nile virus methyltransferase by nucleoside analogs

Hui Chen, Lihui Liu, Susan A. Jones, Nilesh Banavali, Jorden Kass, Zhong Li, Jing Zhang, Laura D. Kramer, Arun K. Ghosh, Hongmin Li

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

46 Scopus citations

Abstract

The flavivirus methyltransferase (MTase) sequentially methylates the N-7 and 2'-O positions of the viral RNA cap (GpppA-RNA→m⁷GpppA-RNA→m⁷GpppAm-RNA), using S-adenosyl-l-methionine (SAM) as a methyl donor. We report here the synthesis and biological evaluation of a series of novel nucleoside analogs. Two of these compounds can effectively and competitively inhibit the WNV MTase with IC₅₀ values in micromolar range and, more importantly, do not inhibit human MTase. The compounds can also suppress the WNV replication in cell culture.

Original language	English (US)
Pages (from-to)	232-239
Number of pages	8
Journal	Antiviral Research
Volume	97
Issue number	3
DOIs	https://doi.org/10.1016/j.antiviral.2012.12.012
State	Published - Mar 2013
Externally published	Yes

Keywords

Antiviral development
Flavivirus NS5
Methyltransferase
RNA cap methylation
West Nile virus

ASJC Scopus subject areas

Pharmacology
Virology

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10.1016/j.antiviral.2012.12.012

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title = "Selective inhibition of the West Nile virus methyltransferase by nucleoside analogs",

abstract = "The flavivirus methyltransferase (MTase) sequentially methylates the N-7 and 2'-O positions of the viral RNA cap (GpppA-RNA→m7GpppA-RNA→m7GpppAm-RNA), using S-adenosyl-l-methionine (SAM) as a methyl donor. We report here the synthesis and biological evaluation of a series of novel nucleoside analogs. Two of these compounds can effectively and competitively inhibit the WNV MTase with IC50 values in micromolar range and, more importantly, do not inhibit human MTase. The compounds can also suppress the WNV replication in cell culture.",

keywords = "Antiviral development, Flavivirus NS5, Methyltransferase, RNA cap methylation, West Nile virus",

author = "Hui Chen and Lihui Liu and Jones, {Susan A.} and Nilesh Banavali and Jorden Kass and Zhong Li and Jing Zhang and Kramer, {Laura D.} and Ghosh, {Arun K.} and Hongmin Li",

note = "Funding Information: This research was partially supported by grants (AI07079201A1 to H.L. and AI 09433501 to L.D.K., A.K.G. and H.L.) from the National Institute of Health (NIH) . The authors would like to thank the Wadsworth Center Tissue Culture Core facility for providing cells and media. We thank Aaron Shatkin at Rutgers, the State University of New Jersey for providing us the plasmid for expression of recombinant human guanine N-7 RNA methyltransferase.",

year = "2013",

month = mar,

doi = "10.1016/j.antiviral.2012.12.012",

language = "English (US)",

volume = "97",

pages = "232--239",

journal = "Antiviral Research",

issn = "0166-3542",

publisher = "Elsevier",

number = "3",

}

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T1 - Selective inhibition of the West Nile virus methyltransferase by nucleoside analogs

AU - Chen, Hui

AU - Liu, Lihui

AU - Jones, Susan A.

AU - Banavali, Nilesh

AU - Kass, Jorden

AU - Li, Zhong

AU - Zhang, Jing

AU - Kramer, Laura D.

AU - Ghosh, Arun K.

AU - Li, Hongmin

N1 - Funding Information: This research was partially supported by grants (AI07079201A1 to H.L. and AI 09433501 to L.D.K., A.K.G. and H.L.) from the National Institute of Health (NIH) . The authors would like to thank the Wadsworth Center Tissue Culture Core facility for providing cells and media. We thank Aaron Shatkin at Rutgers, the State University of New Jersey for providing us the plasmid for expression of recombinant human guanine N-7 RNA methyltransferase.

PY - 2013/3

Y1 - 2013/3

N2 - The flavivirus methyltransferase (MTase) sequentially methylates the N-7 and 2'-O positions of the viral RNA cap (GpppA-RNA→m7GpppA-RNA→m7GpppAm-RNA), using S-adenosyl-l-methionine (SAM) as a methyl donor. We report here the synthesis and biological evaluation of a series of novel nucleoside analogs. Two of these compounds can effectively and competitively inhibit the WNV MTase with IC50 values in micromolar range and, more importantly, do not inhibit human MTase. The compounds can also suppress the WNV replication in cell culture.

AB - The flavivirus methyltransferase (MTase) sequentially methylates the N-7 and 2'-O positions of the viral RNA cap (GpppA-RNA→m7GpppA-RNA→m7GpppAm-RNA), using S-adenosyl-l-methionine (SAM) as a methyl donor. We report here the synthesis and biological evaluation of a series of novel nucleoside analogs. Two of these compounds can effectively and competitively inhibit the WNV MTase with IC50 values in micromolar range and, more importantly, do not inhibit human MTase. The compounds can also suppress the WNV replication in cell culture.

KW - Antiviral development

KW - Flavivirus NS5

KW - Methyltransferase

KW - RNA cap methylation

KW - West Nile virus

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DO - 10.1016/j.antiviral.2012.12.012

M3 - Article

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SN - 0166-3542

VL - 97

SP - 232

EP - 239

JO - Antiviral Research

JF - Antiviral Research

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ER -

Selective inhibition of the West Nile virus methyltransferase by nucleoside analogs

Abstract

Keywords

ASJC Scopus subject areas

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