title: Inhibition of dengue virus RNA synthesis by an adenosine nucleoside.
abstract: We recently reported that (2R,3R,4R,5R)-2-(4-amino-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxy-methyl-tetrahydro-furan-3,4-diol is a potent inhibitor of dengue virus (DENV), with 50% effective concentration (EC(50)) and cytotoxic concentration (CC(50)) values of 0.7 microM and >100 microM, respectively. Here we describe the synthesis, structure-activity relationship, and antiviral characterization of the inhibitor. In an AG129 mouse model, a single-dose treatment of DENV-infected mice with the compound suppressed peak viremia and completely prevented death. Mode-of-action analysis using a DENV replicon indicated that the compound blocks viral RNA synthesis. Recombinant adenosine kinase could convert the compound to a monophosphate form. Suppression of host adenosine kinase, using a specific inhibitor (iodotubercidin) or small interfering RNA (siRNA), abolished or reduced the compound's antiviral activity in cell culture. Studies of rats showed that (14)C-labeled compound was converted to mono-, di-, and triphosphate metabolites in vivo. Collectively, the results suggest that this adenosine inhibitor is phosphorylated to an active (triphosphate) form which functions as a chain terminator for viral RNA synthesis.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, No. 05-01 Chromos, 138670, Singapore.
authors.forename: Yen-Liang
authors.initials: YL
authors.lastname: Chen
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.forename: Jeyaraj
authors.initials: J
authors.lastname: Duraiswamy
authors.forename: Wouter
authors.initials: W
authors.lastname: Schul
authors.forename: Chin Chin
authors.initials: CC
authors.lastname: Lim
authors.forename: Boping
authors.initials: B
authors.lastname: Liu
authors.forename: Hao Ying
authors.initials: HY
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Qing
authors.forename: Andy
authors.initials: A
authors.lastname: Yip
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Wai Ling
authors.initials: WL
authors.lastname: Chan
authors.forename: Hui Pen
authors.initials: HP
authors.lastname: Tan
authors.forename: Melissa
authors.initials: M
authors.lastname: Lo
authors.forename: Sarah
authors.initials: S
authors.lastname: Liung
authors.forename: Ravinder Reddy
authors.initials: RR
authors.lastname: Kondreddi
authors.forename: Ranga
authors.initials: R
authors.lastname: Rao
authors.forename: Helen
authors.initials: H
authors.lastname: Gu
authors.forename: Handan
authors.initials: H
authors.lastname: He
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
mesh_terms: D000241:Adenosine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000248:Adenosine Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008297:Male; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D012367:RNA, Viral / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000998:Antiviral Agents; D034741:RNA, Small Interfering; D012367:RNA, Viral; D000248:Adenosine Kinase; D000241:Adenosine
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