title: An adenosine nucleoside inhibitor of dengue virus.
abstract: 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.
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.forename: Yen-Liang
authors.initials: YL
authors.lastname: Chen
authors.forename: Wouter
authors.initials: W
authors.lastname: Schul
authors.forename: Qing-Yin
authors.initials: QY
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Gu
authors.forename: Jeyaraj
authors.initials: J
authors.lastname: Duraiswamy
authors.forename: Ravinder Reddy
authors.initials: RR
authors.lastname: Kondreddi
authors.forename: Pornwaratt
authors.initials: P
authors.lastname: Niyomrattanakit
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.forename: Hao Ying
authors.initials: HY
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Boping
authors.initials: B
authors.lastname: Liu
authors.forename: Joanne Y H
authors.initials: JY
authors.lastname: Lim
authors.forename: Chuan Young
authors.initials: CY
authors.lastname: Ng
authors.forename: Min
authors.initials: M
authors.lastname: Qing
authors.forename: Chin Chin
authors.initials: CC
authors.lastname: Lim
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: Kai
authors.initials: K
authors.lastname: Lin
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Zou
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Bernard
authors.forename: Christine
authors.initials: C
authors.lastname: Garrett
authors.forename: Karen
authors.initials: K
authors.lastname: Beltz
authors.forename: Min
authors.initials: M
authors.lastname: Dong
authors.forename: Margaret
authors.initials: M
authors.lastname: Weaver
authors.forename: Handan
authors.initials: H
authors.lastname: He
authors.forename: Arkadius
authors.initials: A
authors.lastname: Pichota
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
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; 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*
chemical_list: D000998:Antiviral Agents; D012324:RNA-Dependent RNA Polymerase; D000241:Adenosine