Novel Broad Spectrum Inhibitors Targeting the Flavivirus Methyltransferase

被引:54
作者
Brecher, Matthew [1 ]
Chen, Hui [1 ]
Liu, Binbin [1 ]
Banavali, Nilesh K. [1 ,2 ]
Jones, Susan A. [1 ]
Zhang, Jing [1 ]
Li, Zhong [1 ]
Kramer, Laura D. [1 ,2 ]
Li, Hongmin [1 ,2 ]
机构
[1] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12208 USA
[2] SUNY Albany, Sch Publ Hlth, Dept Biomed Sci, Albany, NY 12201 USA
关键词
NILE-VIRUS METHYLTRANSFERASE; DENGUE VIRUS; RNA CAP; NS5; METHYLATIONS; DISCOVERY; PROTEIN; ASSAY;
D O I
10.1371/journal.pone.0130062
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2'-O positions of the viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here that small molecule compounds, which putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function, were identified by using virtual screening. In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity. The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses. Two of these compounds also exhibited low cytotoxicity and effectively inhibited viral replication in cell-based assays, providing further structural insight into flavivirus MTase inhibition.
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页数:15
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