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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：
Brian V Geisbrecht
金额：
$ 18.75万
依托单位：
KANSAS STATE UNIVERSITY
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：
https://reporter.nih.gov/project-details/8891551
关键词：
Active Sites Acute Adherence Affinity Anti-Inflammatory Agents Anti-inflammatory Autoimmune Diseases Bacteria Basic Science Binding Binding Sites Biochemical Biological Assay Cell surface Chronic Complement Complement 3 Convertase Complement 3b Complement 4b Complement Activation Complement Inactivators Complex Cyclic Peptides Development Disease Dose Enzymes Event Extracellular Domain Extracellular Protein FDA approved Foundations Future Generations Goals Graft Rejection Human Human body Hyperactive behavior Immunity Inflammation Inflammation Mediators Inflammatory Intervention Investigation Lead Lectin Libraries Malignant Neoplasms Mediating Modeling Molecular Mutagenesis Nature Neurodegenerative Disorders Pathway interactions Peptide Hydrolases Peptides Phage Display Pharmaceutical Preparations Play Price Process Protein Binding Protein Family Protein Inhibition Proteins Rare Diseases Regulation Reperfusion Injury Role Route Sepsis Syndrome Series Serine Protease Serpins Site Specificity Staphylococcus aureus Structure Structure-Activity Relationship System Therapeutic Virulent Whole Blood Work alternative pathway complement C3 convertase base biomaterial incompatibility complement 4b-binding protein complement C2a complement C3 precursor complement C4c complement pathway complement system design driving force extracellular human disease inhibitor/antagonist insight member neutrophil novel novel strategies pathogen protein structure function public health relevance response screening therapeutic 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.