Inhibition of dengue virus RNA synthesis by an adenosine nucleoside.
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.
Chen
Yen-Liang
YL
Novartis Institute for Tropical Diseases, 10 Biopolis Road, No. 05-01 Chromos, 138670, Singapore.
Yin
Zheng
Z
Duraiswamy
Jeyaraj
J
Schul
Wouter
W
Lim
Chin Chin
CC
Liu
Boping
B
Xu
Hao Ying
HY
Qing
Min
M
Yip
Andy
A
Wang
Gang
G
Chan
Wai Ling
WL
Tan
Hui Pen
HP
Lo
Melissa
M
Liung
Sarah
S
Kondreddi
Ravinder Reddy
RR
Rao
Ranga
R
Gu
Helen
H
He
Handan
H
Keller
Thomas H
TH
Shi
Pei-Yong
PY
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
D000998:Antiviral Agents; D034741:RNA, Small Interfering; D012367:RNA, Viral; D000248:Adenosine Kinase; D000241:Adenosine
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