An adenosine nucleoside inhibitor of dengue virus.
Dengue virus (DENV), a mosquito-borne flavivirus, is a major public health threat. The virus poses risk to 2.5 billion people worldwide and causes 50 to 100 million human infections each year. Neither a vaccine nor an antiviral therapy is currently available for prevention and treatment of DENV infection. Here, we report a previously undescribed adenosine analog, NITD008, that potently inhibits DENV both in vitro and in vivo. In addition to the 4 serotypes of DENV, NITD008 inhibits other flaviviruses, including West Nile virus, yellow fever virus, and Powassan virus. The compound also suppresses hepatitis C virus, but it does not inhibit nonflaviviruses, such as Western equine encephalitis virus and vesicular stomatitis virus. A triphosphate form of NITD008 directly inhibits the RNA-dependent RNA polymerase activity of DENV, indicating that the compound functions as a chain terminator during viral RNA synthesis. NITD008 has good in vivo pharmacokinetic properties and is biologically available through oral administration. Treatment of DENV-infected mice with NITD008 suppressed peak viremia, reduced cytokine elevation, and completely prevented the infected mice from death. No observed adverse effect level (NOAEL) was achieved when rats were orally dosed with NITD008 at 50 mg/kg daily for 1 week. However, NOAEL could not be accomplished when rats and dogs were dosed daily for 2 weeks. Nevertheless, our results have proved the concept that a nucleoside inhibitor could be developed for potential treatment of flavivirus infections.
Yin
Zheng
Z
Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore.
Chen
Yen-Liang
YL
Schul
Wouter
W
Wang
Qing-Yin
QY
Gu
Feng
F
Duraiswamy
Jeyaraj
J
Kondreddi
Ravinder Reddy
RR
Niyomrattanakit
Pornwaratt
P
Lakshminarayana
Suresh B
SB
Goh
Anne
A
Xu
Hao Ying
HY
Liu
Wei
W
Liu
Boping
B
Lim
Joanne Y H
JY
Ng
Chuan Young
CY
Qing
Min
M
Lim
Chin Chin
CC
Yip
Andy
A
Wang
Gang
G
Chan
Wai Ling
WL
Tan
Hui Pen
HP
Lin
Kai
K
Zhang
Bo
B
Zou
Gang
G
Bernard
Kristen A
KA
Garrett
Christine
C
Beltz
Karen
K
Dong
Min
M
Weaver
Margaret
M
He
Handan
H
Pichota
Arkadius
A
Dartois
Veronique
V
Keller
Thomas H
TH
Shi
Pei-Yong
PY
D000241:Adenosine / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002522:Chlorocebus aethiops; D003715:Dengue / Q000188:drug therapy*; D003716:Dengue Virus / Q000378:metabolism*; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008297:Male; D051379:Mice; D015394:Molecular Structure; D019055:No-Observed-Adverse-Effect Level; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D014709:Vero Cells; D014766:Viremia / Q000188:drug therapy*
D000998:Antiviral Agents; D012324:RNA-Dependent RNA Polymerase; D000241:Adenosine