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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >An adenosine nucleoside inhibitor of dengue virus
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An adenosine nucleoside inhibitor of dengue virus

机译：登革病毒腺苷核苷抑制剂

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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 pharmaco-kinetic 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.
机译：登革热病毒（DENV）是一种由蚊子传播的黄病毒，是主要的公共卫生威胁。该病毒给全球25亿人带来风险，每年导致50到1亿人感染。当前没有疫苗和抗病毒疗法可用于预防和治疗DENV感染。在这里，我们报告以前未描述的腺苷类似物NITD008，在体外和体内均可有效抑制DENV。除DENV的4种血清型外，NITD008还抑制其他黄病毒，包括西尼罗河病毒，黄热病病毒和Powassan病毒。该化合物还抑制丙型肝炎病毒，但不抑制非黄病毒，例如西方马脑炎病毒和水疱性口炎病毒。 NITD008的三磷酸酯形式直接抑制DENV的RNA依赖性RNA聚合酶活性，表明该化合物在病毒RNA合成过程中起链终止剂的作用。 NITD008具有良好的体内药代动力学特性，可通过口服给药获得。用NITD008处理DENV感染的小鼠可抑制病毒血症峰值，降低细胞因子升高并完全防止感染的小鼠死亡。当大鼠每天口服NITD008以50 mg / kg的剂量给药1周时，未观察到不良反应水平（NOAEL）。但是，当每天给大鼠和狗给药2周时，NOAEL无法完成。尽管如此，我们的结果证明了可以开发出一种核苷抑制剂来潜在治疗黄病毒感染的概念。

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  • 作者

    Zheng Yin; Yen-Liang Chen; Wouter Schul; Qing-Yin Wang; Feng Gu; Jeyaraj Duraiswamy; Ravinder Reddy Kondreddi; Pornwaratt Niyomrattanakit; Suresh B. Lakshminarayana; Anne Goh; Hao Ying Xu; Wei Liu; Boping Liu; Joanne Y. H. Lim; Chuan Young Ng; Min Qing; Chin Chin Lim; Andy Yip; Gang Wang; Wai Ling Chan; Hui Pen Tan; Kai Lin; Bo Zhang; Gang Zou; Kristen A. Bernard; Christine Garrett; Karen Beltz; Min Dong; Margaret Weaver; Handan He; Arkadius Pichota; Veronique Dartois; Thomas H. Keller; Pei-Yong Shi;

  • 作者单位

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore College of Pharmacy & The State key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Wadsworth Center, New York State Department of Health, Albany, NY 12208;

    Wadsworth Center, New York State Department of Health, Albany, NY 12208;

    Wadsworth Center, New York State Department of Health, Albany, NY 12208;

    Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936-3142;

    Novartis Pharma AG, 4057 Basel, Switzerland;

    Novartis Pharma AG, CH-4132 Muttenz, Switzerland;

    Novartis Institutes for Biomedical Research, Inc., Cambridge, MA 02139;

    Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936-3142;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

    Novartis Institute for Tropical Diseases, Singapore, 138670, Singapore;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    antiviral therapy; flavivirus; viral replication;

    机译：抗病毒治疗;黄病毒病毒复制;

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