@article{2f8954e99d8e455a92ffa1ffe53ca1d0,
title = "Identification and Characterization of Novel Broad-Spectrum Inhibitors of the Flavivirus Methyltransferase",
abstract = "Flavivirus methyltransferase (MTase) is essential for viral replication. Here we report the identification of small molecules through virtual screening that putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function. Six of these computationally predicted binders were identified to show significant MTase inhibition with low micromolar inhibitory activity. The most active compounds showed broad-spectrum activity against the MTase proteins of other flaviviruses. Two of these compounds also showed low cytotoxicity and high antiviral efficacy in cell-based assays. Competitive binding analyses indicated that the inhibitors performed their inhibitory function through competitive binding to the SAM cofactor binding site of the MTase. The crystal structure of the MTase-inhibitor complex further supports the mode of action and provides routes for their further optimization as flavivirus MTase inhibitors.",
keywords = "antiviral development, flavivirus NS5, methyltransferase, RNA cap methylation, West Nile virus",
author = "Matthew Brecher and Hui Chen and Zhong Li and Banavali, {Nilesh K.} and Jones, {Susan A.} and Jing Zhang and Kramer, {Laura D.} and Hongmin Li",
note = "Funding Information: This research was supported by grants (AI09433501 to L.D.K and H.L.) from the National Institute of Health (NIH)). M.B. was partially supported by the NIH Biodefense and Emerging Infectious Disease training grant AI055429. We thank Dr. Vivian Stojanoff at the Brookhaven National Laboratory for helps during X-ray data collection. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393) . The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. We thank the Wadsworth Center Tissue Culture Core facility for providing cells and media. Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",
year = "2016",
month = jan,
day = "8",
doi = "10.1021/acsinfecdis.5b00070",
language = "English (US)",
volume = "1",
pages = "340--349",
journal = "ACS Infectious Diseases",
issn = "2373-8227",
publisher = "American Chemical Society",
number = "8",
}