title: Novel Broad Spectrum Inhibitors Targeting the Flavivirus Methyltransferase.
abstract: 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.
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brecher
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America.
authors.forename: Binbin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America; Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, PO Box 509, New York, 12201, United States of America.
authors.forename: Nilesh K
authors.initials: NK
authors.lastname: Banavali
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America; Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, PO Box 509, New York, 12201, United States of America.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Kramer
authors.affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America; Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, PO Box 509, New York, 12201, United States of America.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Li
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D005416:Flavivirus / Q000187:drug effects* / Q000201:enzymology; D018177:Flavivirus Infections / Q000188:drug therapy*; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D012315:RNA Caps / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C096041:NS5 protein, flavivirus; D012315:RNA Caps; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D008780:Methyltransferases