An adenosine nucleoside inhibitor of dengue virus

被引：312

作者：

Yin, Zheng ^{[1
]}

Chen, Yen-Liang ^{[1
]}

Schul, Wouter ^{[1
]}

Wang, Qing-Yin ^{[1
]}

Gu, Feng ^{[1
]}

Duraiswamy, Jeyaraj ^{[1
]}

Kondreddi, Ravinder Reddy ^{[1
]}

Niyomrattanakit, Pornwaratt ^{[1
]}

Lakshminarayana, Suresh B. ^{[1
]}

Goh, Anne ^{[1
]}

Xu, Hao Ying ^{[1
]}

Liu, Wei ^{[1
]}

Liu, Boping ^{[1
]}

Lim, Joanne Y. H. ^{[1
]}

Ng, Chuan Young ^{[1
]}

Qing, Min ^{[1
]}

Lim, Chin Chin ^{[1
]}

Yip, Andy ^{[1
]}

Wang, Gang ^{[1
]}

Chan, Wai Ling ^{[1
]}

Tan, Hui Pen ^{[1
]}

Lin, Kai ^{[2
]}

Zhang, Bo ^{[3
]}

Zou, Gang ^{[3
]}

Bernard, Kristen A. ^{[3
]}

Garrett, Christine ^{[4
]}

Beltz, Karen ^{[5
]}

Dong, Min ^{[6
]}

Weaver, Margaret ^{[2
]}

He, Handan ^{[4
]}

Pichota, Arkadius ^{[1
]}

Dartois, Veronique ^{[1
]}

Keller, Thomas H. ^{[1
]}

Shi, Pei-Yong ^{[1
]}

机构：

[1] Novartis Inst Trop Dis, Singapore 138670, Singapore

[2] Novartis Inst Biomed Res Inc, Cambridge, MA 02139 USA

[3] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12208 USA

[4] Novartis Pharmaceut, E Hanover, NJ 07936 USA

[5] Novartis Pharma AG, CH-4057 Basel, Switzerland

[6] Novartis Pharma AG, CH-4132 Muttenz, Switzerland

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 48期

关键词：

antiviral therapy; flavivirus; viral replication; WEST-NILE-VIRUS; REPLICATION; PROTEIN; FLAVIVIRUS; POTENT; MODEL; NS2A; NS3;

D O I：

10.1073/pnas.0907010106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：20435 / 20439

页数：5

共 19 条

[1] Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist [J].