The PIP2-virus interface and PI 4-kinase: novel biology and validation targets

PIP2-病毒界面和 PI 4-激酶:新的生物学和验证目标

基本信息

  • 批准号:
    8449564
  • 负责人:
  • 金额:
    $ 102.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-04-01 至 2017-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Our long term objectives are twofold: 1) to use a novel chemical tool set to study a critical host-pathogen inter- face and its role in virus life cycles; 2) We also seek to validate a focused set of targets that can serve as the basis for future chemical screens to identify drug candidates, as well as an annotate all available pathogen genomes that are susceptible to chemical inhibition of these targets. Phosphoinositide (PI) 4-kinase activity is essential for generating specific phosphoinositides such as PI-4,5-bisphosphate (PI(4,5)P2, or "PIP2"). We discovered a novel PIP2 binding motif within the hepatitis C virus (HCV) NS5A protein. This motif, termed a Basic Amino Acid PIP2 Pincer (or "BAAPP domain"), mediates specific interaction with PIP2, and point mutations in the BAAPP domain abrogate PIP2 binding and HCV RNA replication. Similar BAAPP domains are found in pathogens as diverse as rhinovirus and P. falciparum. Finally, small molecules recently developed to inhibit PIP2 production without host toxicity by targeting specific PI 4-kinase (PI4K) family members-the PI4KIII alpha (PI4KIII¿) and beta (PI4KIII¿) isoforms--potently inhibit HCV replication in vitro (e.g. inhibitor PT423 exhibits IC50 365 nM; CC50 > 10microM), and display comparable activity against several BAAPP domain-containing pathogens tested to date. We now seek to: 1) Further probe and exploit the role of PI4KIII in the HCV life cycle by: a) determining the effect of PT423 treatment on HCV replication complex integrity and enzymatic activity using biochemical fractionation and membrane-associated replicase assays; b) evaluating the potential for inhibitors of PI4KIII to synergize with other classes of anti-HCV agents targeting replicase complex assembly and function; c) providing proof-of-concept that PI4KIII inhibitors can inhibit multidrug resistant viruses by determining the susceptibility to PT423 of HCV variants resistant to various classes of HCV antivirals; 2) Further validate PI4KIII as a target for future drug screening efforts by: a) performing cellular pull-down assays, in the presence or absence of HCV, with PT423-linked beads coupled with mass spectrometry to identify candidate off-target proteins and how that spectrum might change in the face of viral infection; b) further validating the mechanism of action of our model PI4KIII inhibitors by studying PT423 levels required for HCV inhibition in the presence of either siRNA against PI4KIII¿, or PI4KIII¿ mutants with engineered candidate mutations conferring resistance to PT423; 3) Determine the critical BAAPP domain features that define susceptibility to chemical inhibitors of PI4KIII by: a) determining the crystal structure of full length NS5A, with and withou PIP2; b) performing a structure/function analysis of BAAPP domain peptides to define their key determinants of PIP2 binding using quartz crystal microbalance, fluorescence polarization, and the nuclear magnetic resonance structures of the peptides; c) developing an algorithm to automatically identify the above determined key features of a PIP2 binding BAAPP domain within databases of all available pathogen genomes; d) providing proof-of-concept that identified pathogens are susceptible to inhibition with PI4KIII inhibitors.
描述(由申请人提供):我们的长期目标有两个:1)使用一种新的化学工具集来研究宿主-病原体的关键界面及其在病毒生命周期中的作用;2)我们还寻求验证一组重点目标,这些目标可以作为未来的基础

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(4)

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JEFFREY S GLENN其他文献

JEFFREY S GLENN的其他文献

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{{ truncateString('JEFFREY S GLENN', 18)}}的其他基金

Oral small molecule inhibitors of NSP4-mediated membrane-associated RNA replication of SARS-CoV-2 and other RNA viruses
NSP4 介导的 SARS-CoV-2 和其他 RNA 病毒膜相关 RNA 复制的口服小分子抑制剂
  • 批准号:
    10514275
  • 财政年份:
    2022
  • 资助金额:
    $ 102.08万
  • 项目类别:
Development of outpatient antiviral cocktails against SARS-CoV-2 and other potential pandemic RNA viruses.
开发针对 SARS-CoV-2 和其他潜在大流行性 RNA 病毒的门诊抗病毒鸡尾酒。
  • 批准号:
    10514264
  • 财政年份:
    2022
  • 资助金额:
    $ 102.08万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10514265
  • 财政年份:
    2022
  • 资助金额:
    $ 102.08万
  • 项目类别:
Programmable antivirals: Targeting viral RNA secondary structures with LNAs and small molecules
可编程抗病毒药物:利用 LNA 和小分子靶向病毒 RNA 二级结构
  • 批准号:
    10514269
  • 财政年份:
    2022
  • 资助金额:
    $ 102.08万
  • 项目类别:
Optimizing a small molecule inhibitor of SARS-CoV-2 replication and associated cytokine storm
优化 SARS-CoV-2 复制和相关细胞因子风暴的小分子抑制剂
  • 批准号:
    10681264
  • 财政年份:
    2021
  • 资助金额:
    $ 102.08万
  • 项目类别:
Optimizing a small molecule inhibitor of SARS-CoV-2 replication and associated cytokine storm
优化 SARS-CoV-2 复制和相关细胞因子风暴的小分子抑制剂
  • 批准号:
    10470714
  • 财政年份:
    2021
  • 资助金额:
    $ 102.08万
  • 项目类别:
Optimizing a small molecule inhibitor of SARS-CoV-2 replication and associated cytokine storm
优化 SARS-CoV-2 复制和相关细胞因子风暴的小分子抑制剂
  • 批准号:
    10187861
  • 财政年份:
    2021
  • 资助金额:
    $ 102.08万
  • 项目类别:
Advancing a broad-spectrum anti-influenza A virus RNA packaging inhibitor to an IND
将广谱抗甲型流感病毒 RNA 包装抑制剂推进 IND
  • 批准号:
    10165884
  • 财政年份:
    2020
  • 资助金额:
    $ 102.08万
  • 项目类别:
Rapid development of SARS-CoV-2 specific therapeutics that leverage virus specific RNA elements
利用病毒特异性 RNA 元件快速开发 SARS-CoV-2 特异性疗法
  • 批准号:
    10115505
  • 财政年份:
    2020
  • 资助金额:
    $ 102.08万
  • 项目类别:
Advancing a broad-spectrum anti-influenza A virus RNA packaging inhibitor to an IND
将广谱抗甲型流感病毒 RNA 包装抑制剂推进 IND
  • 批准号:
    9750617
  • 财政年份:
    2017
  • 资助金额:
    $ 102.08万
  • 项目类别:

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