High throughput screening of orthosteric inhibitors of flavivirus protease

黄病毒蛋白酶正构抑制剂的高通量筛选

基本信息

  • 批准号:
    10318299
  • 负责人:
  • 金额:
    $ 56.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-02-15 至 2023-01-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract: Many flaviviruses such as Dengue virus, Zika virus, West Nile virus, and Yellow Fever virus cause significant human diseases. However, no clinically approved antiviral therapy is available for treatment of flavivirus infections. Therefore, the development of vaccines and antiviral agents for prevention and treatment of flavivirus infections is a clear public health priority. The long- range goal of this proposal is to address this need by developing a new system to identify, screen and validate a class of potential flavivirus inhibitors, and successfully identify and analyze candidate compounds that show promise in disrupting viral survival. During flaviviral infection of the host cell, a single viral polyprotein is synthesized from the viral genome. This polyprotein is cleaved into its component proteins by a combination of host cell proteases and a two-component viral protease, encoded in genes NS2B and NS3. The function of this viral protease is indispensable for virus assembly and replication. The objectives of this project are to develop innovative high throughput screening strategies to identify and characterize compounds that orthosterically inhibit the function of the critical protease NS2B- NS3. To achieve project objectives, in Specific Aim 1, we will develop and perform novel high- throughput screening primary, secondary, and tertiary assays capable of screening large chemical libraries to identify orthosteric inhibitors. In Specific Aim 2, after optimizing these assays, we will perform large-scale HTS to screen a compound library of >400,000 compounds for potential protease inhibitor candidates, employing five levels of screening to fully eliminate false positives. In Specific Aim 3, we will evaluate the efficacy of the resulting candidate compounds for their capacity to block protease activity, and determined their modes of actions. Lead compounds against the protease will be tested for cellular toxicity, reduction of flavivirus titer in cell culture, resistant variants, and limited structure-activity relationship. We will ultimately test the toxicity, pharmacokinetics, and efficacy in live animals for the most potent compounds. We anticipate the outcome of this study will be the generation of crucial new information on flavivirus inhibitor-enzyme interaction at structurally significant sites. This creates the potential for identifying novel classes of flaviviral inhibitors, suitable for addressing the global public health need for new antiviral agents to fight flaviviruses.
项目总结/文摘:

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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HONGMIN LI其他文献

HONGMIN LI的其他文献

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{{ truncateString('HONGMIN LI', 18)}}的其他基金

Development of Inhibitors Targeting Flavivirus Methyltransferase
黄病毒甲基转移酶抑制剂的开发
  • 批准号:
    10636605
  • 财政年份:
    2023
  • 资助金额:
    $ 56.34万
  • 项目类别:
Discovery of therapeutics against Cryptococcosis by Repurposing Pharmaceutical Libraries
通过重新利用药物库发现隐球菌病的治疗方法
  • 批准号:
    10308245
  • 财政年份:
    2019
  • 资助金额:
    $ 56.34万
  • 项目类别:
High throughput screening of the Prp8 intein splicing inhibitors for pathogenic fungi
病原真菌 Prp8 内含肽剪接抑制剂的高通量筛选
  • 批准号:
    10319642
  • 财政年份:
    2018
  • 资助金额:
    $ 56.34万
  • 项目类别:
High throughput screening of orthosteric inhibitors of flavivirus protease
黄病毒蛋白酶正构抑制剂的高通量筛选
  • 批准号:
    10376239
  • 财政年份:
    2018
  • 资助金额:
    $ 56.34万
  • 项目类别:
High throughput screening of the Prp8 intein splicing inhibitors for pathogenic fungi
病原真菌 Prp8 内含肽剪接抑制剂的高通量筛选
  • 批准号:
    10382470
  • 财政年份:
    2018
  • 资助金额:
    $ 56.34万
  • 项目类别:
High throughput screening of orthosteric inhibitors of flavivirus protease
黄病毒蛋白酶正构抑制剂的高通量筛选
  • 批准号:
    9538444
  • 财政年份:
    2017
  • 资助金额:
    $ 56.34万
  • 项目类别:
New Use of Old Drugs for Zika Virus
老药新用途对抗寨卡病毒
  • 批准号:
    9412543
  • 财政年份:
    2017
  • 资助金额:
    $ 56.34万
  • 项目类别:
Mechanism of MALT1 Regulation by a Novel Ubiquitin Ligase
新型泛素连接酶调节 MALT1 的机制
  • 批准号:
    9053450
  • 财政年份:
    2015
  • 资助金额:
    $ 56.34万
  • 项目类别:
Mechanism of MALT1 Regulation by a Novel Ubiquitin Ligase
新型泛素连接酶调节 MALT1 的机制
  • 批准号:
    8821943
  • 财政年份:
    2015
  • 资助金额:
    $ 56.34万
  • 项目类别:
The West Nile virus methyltransferase
西尼罗河病毒甲基转移酶
  • 批准号:
    7842651
  • 财政年份:
    2009
  • 资助金额:
    $ 56.34万
  • 项目类别:

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