Inhibition of dengue virus RNA synthesis by an adenosine nucleoside.
Basic Information
ID: ALA1629694
Journal: Antimicrob Agents Chemother
Title: Inhibition of dengue virus RNA synthesis by an adenosine nucleoside.
Authors: Chen YL, Yin Z, Duraiswamy J, Schul W, Lim CC, Liu B, Xu HY, Qing M, Yip A, Wang G, Chan WL, Tan HP, Lo M, Liung S, Kondreddi RR, Rao R, Gu H, He H, Keller TH, Shi PY.
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.
CiteXplore: 20457821
DOI: 10.1128/aac.00140-10
Patent ID: ┄