title: Small molecule inhibitors that selectively block dengue virus methyltransferase.
abstract: Crystal structure analysis of Flavivirus methyltransferases uncovered a flavivirus-conserved cavity located next to the binding site for its cofactor, S-adenosyl-methionine (SAM). Chemical derivatization of S-adenosyl-homocysteine (SAH), the product inhibitor of the methylation reaction, with substituents that extend into the identified cavity, generated inhibitors that showed improved and selective activity against dengue virus methyltransferase (MTase), but not related human enzymes. Crystal structure of dengue virus MTase with a bound SAH derivative revealed that its N6-substituent bound in this cavity and induced conformation changes in residues lining the pocket. These findings demonstrate that one of the major hurdles for the development of methyltransferase-based therapeutics, namely selectivity for disease-related methyltransferases, can be overcome.
authors.affiliation: Novartis Institute for Tropical Diseases, 05-01 Chromos, Singapore. siew_pheng.lim@novartis.com
authors.forename: Siew Pheng
authors.initials: SP
authors.lastname: Lim
authors.forename: Louis Sebastian
authors.initials: LS
authors.lastname: Sonntag
authors.forename: Christian
authors.initials: C
authors.lastname: Noble
authors.forename: Shahul H
authors.initials: SH
authors.lastname: Nilar
authors.forename: Ru Hui
authors.initials: RH
authors.lastname: Ng
authors.forename: Gang
authors.initials: G
authors.lastname: Zou
authors.forename: Paul
authors.initials: P
authors.lastname: Monaghan
authors.forename: Ka Yan
authors.initials: KY
authors.lastname: Chung
authors.forename: Hongping
authors.initials: H
authors.lastname: Dong
authors.forename: Boping
authors.initials: B
authors.lastname: Liu
authors.forename: Christophe
authors.initials: C
authors.lastname: Bodenreider
authors.forename: Gladys
authors.initials: G
authors.lastname: Lee
authors.forename: Mei
authors.initials: M
authors.lastname: Ding
authors.forename: Wai Ling
authors.initials: WL
authors.lastname: Chan
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Yap Li
authors.initials: YL
authors.lastname: Jian
authors.forename: Alexander Theodore
authors.initials: AT
authors.lastname: Chao
authors.forename: Julien
authors.initials: J
authors.lastname: Lescar
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.forename: T R
authors.initials: TR
authors.lastname: Vedananda
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003715:Dengue / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D003716:Dengue Virus / Q000201:enzymology* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D012436:S-Adenosylmethionine; D008780:Methyltransferases; C055097:mRNA (guanine(N7))-methyltransferase