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.
authors.affiliation: Wadsworth Center, New York State Department of Health , 120 New Scotland Avenue, Albany, New York 12208, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brecher
authors.affiliation: Wadsworth Center, New York State Department of Health , 120 New Scotland Avenue, Albany, New York 12208, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Wadsworth Center, New York State Department of Health , 120 New Scotland Avenue, Albany, New York 12208, United States.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Wadsworth Center, New York State Department of Health , 120 New Scotland Avenue, Albany, New York 12208, United States.|Department of Biomedical Sciences, School of Public Health, State University of New York , P.O. Box 509, Albany, New York 12201 United States.
authors.forename: Nilesh K
authors.initials: NK
authors.lastname: Banavali
authors.affiliation: Wadsworth Center, New York State Department of Health , 120 New Scotland Avenue, Albany, New York 12208, United States.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Wadsworth Center, New York State Department of Health , 120 New Scotland Avenue, Albany, New York 12208, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Wadsworth Center, New York State Department of Health , 120 New Scotland Avenue, Albany, New York 12208, United States.|Department of Biomedical Sciences, School of Public Health, State University of New York , P.O. Box 509, Albany, New York 12201 United States.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Kramer
authors.affiliation: Wadsworth Center, New York State Department of Health , 120 New Scotland Avenue, Albany, New York 12208, United States.|Department of Biomedical Sciences, School of Public Health, State University of New York , P.O. Box 509, Albany, New York 12201 United States.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Li
keywords: RNA cap methylation; West Nile virus; antiviral development; flavivirus NS5; methyltransferase