Inhibition of the Classical & Lectin Complement Pathways by Staphylococcus aureus Eap

古典的抑制

基本信息

  • 批准号:
    8891551
  • 负责人:
  • 金额:
    $ 18.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-01-01 至 2016-12-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Over the last several years, our understanding of the complement evasion mechanisms utilized by pathogens has increased precipitously through the study of the virulent bacterium Staphylococcus aureus. By screening a library of secreted S. aureus proteins in a human whole-blood model of inflammation, we have identified the Extracellular Adherence Protein (Eap) as the first known S. aureus inhibitor of the Classical (CP) and Lectin (LP) pathways of complement. Eap inhibits both of these pathways in a dose-dependent manner that requires formation of high-nanomolar affinity interaction with complement component C4b. This interaction blocks formation of the CP/LP pro-C3 convertase complex (C4b/C2), which dramatically lowers levels of the active CP/LP C3 convertase (C4b/C2a). Using the same whole-blood model, we have also identified Eap as a potent inhibitor of Neutrophil Serine Proteases (NSPs). Unlike conventional serpins, Eap inhibition of NSPs is non-covalent in nature. Furthermore, it occurs through a molecular mechanism distinct from its effects on the complement system since two related proteins, EapH1 and EapH2, also block NSP activity but have no effect on complement. In this proposal, we will investigate the molecular basis for the specificity of Eap's effects on the CP/LP through two Specific Aims: (1) We will characterize the biochemical and structural basis for Eap binding to complement protein C4b, and (2) We will characterize peptides that compete with Eap for C4b binding and determine whether they retain Eap-like inhibitory activities against the CP/LP. We expect that this integrated structure/function and discovery approach will provide new insight into regulation of the CP/LP. In turn, this may hold important clues into the design and optimization of novel complement-targeted, anti-inflammatory therapeutics in the future.


项目成果

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Brian V Geisbrecht其他文献

Brian V Geisbrecht的其他文献

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{{ truncateString('Brian V Geisbrecht', 18)}}的其他基金

Novel Enzyme Inhibitors in the Innate Immune Evasion Repertoire of Staphylococci
葡萄球菌先天免疫逃避库中的新型酶抑制剂
  • 批准号:
    10395608
  • 财政年份:
    2021
  • 资助金额:
    $ 18.75万
  • 项目类别:
Novel Enzyme Inhibitors in the Innate Immune Evasion Repertoire of Staphylococci
葡萄球菌先天免疫逃避库中的新型酶抑制剂
  • 批准号:
    10576908
  • 财政年份:
    2021
  • 资助金额:
    $ 18.75万
  • 项目类别:
Novel Enzyme Inhibitors in the Innate Immune Evasion Repertoire of Staphylococci
葡萄球菌先天免疫逃避库中的新型酶抑制剂
  • 批准号:
    10166534
  • 财政年份:
    2021
  • 资助金额:
    $ 18.75万
  • 项目类别:
Novel Enzyme Inhibitors in the Immune Evasion Repertoire of Staphylococcus aureus (Equipment Supplement)
金黄色葡萄球菌免疫逃逸的新型酶抑制剂(设备补充)
  • 批准号:
    10796329
  • 财政年份:
    2021
  • 资助金额:
    $ 18.75万
  • 项目类别:
Structure/Function Studies of LILRs Enabled by a Bacterially-Derived Ligand
由细菌衍生的配体实现的 LILR 的结构/功能研究
  • 批准号:
    10308089
  • 财政年份:
    2020
  • 资助金额:
    $ 18.75万
  • 项目类别:
Novel Staphylococcal Inhibitors of Neutrophil Granule Enzymes
新型葡萄球菌中性粒细胞颗粒酶抑制剂
  • 批准号:
    9462166
  • 财政年份:
    2017
  • 资助金额:
    $ 18.75万
  • 项目类别:
Novel Staphylococcal Inhibitors of Neutrophil Granule Enzymes
新型葡萄球菌中性粒细胞颗粒酶抑制剂
  • 批准号:
    9906231
  • 财政年份:
    2017
  • 资助金额:
    $ 18.75万
  • 项目类别:
Cheminformatic Discovery of Alternative Pathway C3 Pro-Convertase Inhibitors
替代途径 C3 前转化酶抑制剂的化学信息学发现
  • 批准号:
    8877399
  • 财政年份:
    2014
  • 资助金额:
    $ 18.75万
  • 项目类别:
Cheminformatic Discovery of Alternative Pathway C3 Pro-Convertase Inhibitors
替代途径 C3 前转化酶抑制剂的化学信息学发现
  • 批准号:
    8772480
  • 财政年份:
    2014
  • 资助金额:
    $ 18.75万
  • 项目类别:
Structure Function Analysis of Staphylococcal Complement Inhibitors
葡萄球菌补体抑制剂的结构功能分析
  • 批准号:
    7382408
  • 财政年份:
    2008
  • 资助金额:
    $ 18.75万
  • 项目类别:

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