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Novel Staphylococcal Inhibitors of Neutrophil Granule Enzymes

新型葡萄球菌中性粒细胞颗粒酶抑制剂

基本信息

批准号：
9462166
负责人：
Brian V Geisbrecht
金额：
$ 28.88万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9462166
关键词：
Acids Acute Adult Respiratory Distress Syndrome Affinity Animals Anti-Bacterial Agents Anti-inflammatory Area Arterial Fatty Streak Atherosclerosis Azurophilic Granule Bacteria Basic Science Binding Biochemical Biochemistry Biological Assay Blood Cardiovascular system Cells Chronic Chronic Obstructive Airway Disease Cleaved cell Collaborations Complex Cytoplasmic Granules Cytosol Data Development Digestion Disease Environment Enzymes Equilibrium Event Evolution Extracellular Matrix Family Fostering Foundations Future Goals Gram-Positive Bacteria Health Heart Human Human body Hydrogen Peroxide Immune Immune Evasion Infection Inflammation Inflammatory Innate Immune Response Innate Immune System Invaded Laboratories Lead Length Leukocyte Elastase Leukocytes Life Low-Density Lipoproteins Mediating Methods Modeling Molecular Conformation Morphology Mutagenesis Neutrophil Activation Pathologic Pattern Peptide Hydrolases Periodicity Peroxidases Play Prevention strategy Process Property Protease Inhibitor Protein Dynamics Proteins Pulmonary Emphysema Research Respiratory Burst Respiratory System Rheumatoid Arthritis Role Sequence Homology Series Serine Protease Serine Proteinase Inhibitors Site Staphylococcal Infections Staphylococcus aureus Stimulus Structure Structure-Activity Relationship Surface System Tertiary Protein Structure Testing Therapeutic Thrombus Tissues Virulence Work base chymotrypsin cytotoxic design extracellular healing heme a human disease inhibitor/antagonist nanomolar neutrophil novel novel strategies oxidative damage pathogen prevent public health relevance response synthetic peptide therapeutic target

项目摘要

Project Abstract/Summary (Project Description) The human body relies on neutrophils to provide a sterilizing innate immune response against bacterial pathogens. Although neutrophils circulate inside the blood in a quiescent state, they are rapidly activated in reponse to a number of biochemical patterns which signify either that potential pathogens are present or that cellular damage has occured. Activation of neutrophils results in remarkable changes in their morphology, and triggers mobilization and secretion of their cytosolic granules. It is these granules which contain critical components of the neutrophil’s anti-bacterial arsenal. Two of the most abudant components of these granules are the enzyme myeloperoxidase (MPO), which converts hydrogen peroxide into cytotoxic hypohalous acids, and a series of chymotrypsin-like serine proteases (NSPs), which can directly attack the pathogen cell by cleaving proteins that are either exposed on its surface or secreted into the environment. Together, the combined action of MPO and NSPs form the foundation of neutrophil-mediated innate defense against invading bacteria. As a consequence of host/pathogen co-evolution, the Gram-positive bacterium Staphylococcus aureus has developed a powerful array of small protein inhibitors that effectively block many of the critical components of the human innate immune response. In this regard, we recently identified three secreted staphylococcal proteins, called Eap, EapH1, and EapH2 (denoted “EAP proteins”), which potently inhibit NSPs, as well as a novel staphylococccal inhibitior of MPO, called SPIN. Through collaborative efforts, we have established that both EAP proteins and SPIN are required for maximal S. aureus virulence in animal infection models. In this project, we will use a synergistic series of crystallographic and solution NMR methods, physical biochemistry approaches, and activity assays to provide detailed structure/function information on these novel staphylococcal inhibitors of neutrophil granule enzymes. We will accomplish this overall goal through two concurrent Specific Aims. In the first Aim, we will investigate the structural basis for the selectivity of EAP domains toward NSPs, examine whether changes in protein dynamics influence EAP/NSP interactions, and define a structure/activity relationship for NSP inhibition by EAP domain proteins. In the second Aim, we will determine the structural basis for SPIN/MPO binding, examine whether SPIN undergoes changes in conformation upon interaction with MPO, and define the biochemical determinants which mediate MPO inhibition by SPIN. Finally, since NSPs and MPO are known to play signifcant roles in damaging host cells and tissues in a number of human inflammatory diseases, we will explore whether synthetic peptides based upon the structures of EAP proteins and SPIN bound to their targets can mimic the therapeutically-valuable activities of these staphylococcal immune evasion proteins. By completing this research plan, we will lay the basic science foundation for future development of anti-bacterial and anti-inflammatory therapies based upon the information that we uncover here.

项目摘要/总结（项目说明）