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
- 来源:
- 关键词:Active SitesAcuteAdherenceAffinityAnti-Inflammatory AgentsAnti-inflammatoryAutoimmune DiseasesBacteriaBasic ScienceBindingBinding SitesBiochemicalBiological AssayCell surfaceChronicComplementComplement 3 ConvertaseComplement 3bComplement 4bComplement ActivationComplement InactivatorsComplexCyclic PeptidesDevelopmentDiseaseDoseEnzymesEventExtracellular DomainExtracellular ProteinFDA approvedFoundationsFutureGenerationsGoalsGraft RejectionHumanHuman bodyHyperactive behaviorImmunityInflammationInflammation MediatorsInflammatoryInterventionInvestigationLeadLectinLibrariesMalignant NeoplasmsMediatingModelingMolecularMutagenesisNatureNeurodegenerative DisordersPathway interactionsPeptide HydrolasesPeptidesPhage DisplayPharmaceutical PreparationsPlayPriceProcessProtein BindingProtein FamilyProtein InhibitionProteinsRare DiseasesRegulationReperfusion InjuryRoleRouteSepsis SyndromeSeriesSerine ProteaseSerpinsSiteSpecificityStaphylococcus aureusStructureStructure-Activity RelationshipSystemTherapeuticVirulentWhole BloodWorkalternative pathway complement C3 convertasebasebiomaterial incompatibilitycomplement 4b-binding proteincomplement C2acomplement C3 precursorcomplement C4ccomplement pathwaycomplement systemdesigndriving forceextracellularhuman diseaseinhibitor/antagonistinsightmemberneutrophilnovelnovel strategiespathogenprotein structure functionpublic health relevanceresponsescreeningtherapeutic target
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.
描述(由申请方提供):在过去几年中,通过对强毒细菌金黄色葡萄球菌的研究,我们对病原体利用的补体逃避机制的理解急剧增加。通过筛选分泌型S.金黄色葡萄球菌蛋白在人全血炎症模型中的表达,我们已经鉴定了细胞外粘附蛋白(Eap)作为第一个已知的金黄色葡萄球菌。金黄色葡萄球菌补体经典(CP)和凝集素(LP)途径的抑制剂。Eap以剂量依赖性方式抑制这两种途径,需要与补体成分C4 b形成高纳摩尔亲和力相互作用。这种相互作用阻断CP/LP pro-C3转化酶复合物(C4 b/C2)的形成,这显著降低了活性CP/LP C3转化酶(C4 b/C2 a)的水平。使用相同的全血模型,我们还将Eap鉴定为神经元丝氨酸蛋白酶(NSP)的有效抑制剂。与常规丝氨酸蛋白酶抑制剂不同,NSP的Eap抑制本质上是非共价的。此外,它通过与其对补体系统的作用不同的分子机制发生,因为两种相关蛋白EapH 1和EapH 2也阻断NSP活性,但对补体没有影响。在这个提议中,我们将通过两个特定的目的来研究Eap对CP/LP作用的特异性的分子基础:(1)我们将表征Eap与补体蛋白C4 b结合的生物化学和结构基础,以及(2)我们将表征与Eap竞争C4 b结合的肽,并确定它们是否保留对CP/LP的Eap样抑制活性。我们期望这种整合的结构/功能和发现方法将为CP/LP的调控提供新的见解。反过来,这可能为未来新型补体靶向抗炎治疗的设计和优化提供重要线索。
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(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Brian V Geisbrecht其他文献
Brian V Geisbrecht的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 18.75万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 18.75万 - 项目类别:
Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 18.75万 - 项目类别:
Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 18.75万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 18.75万 - 项目类别:
Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 18.75万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 18.75万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 18.75万 - 项目类别:
Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 18.75万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
- 批准号:
484000 - 财政年份:2023
- 资助金额:
$ 18.75万 - 项目类别:
Operating Grants