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Optimizing the immune response by targeting the Sts enzymes

通过针对 Sts 酶优化免疫反应

基本信息

批准号：
10305609
负责人：
NICHOLAS A CARPINO
金额：
$ 56.35万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305609
关键词：
Active Sites Animals Binding Biological Biological Assay Candida albicans Cells Chemicals Clinical Clinical Protocols Complex Crystallization Data Development Enzymes Foundations Francisella tularensis Goals Immune response Immune system Immunomodulators Infection Inflammation Innate Immune System Kinetics Lead Leukocytes Libraries Mammalian Cell Measures Mediating Methods Modeling Morbidity - disease rate Mus Outcome Pathogenicity Phagocytes Pharmaceutical Preparations Phenotype Phosphoric Monoester Hydrolases Play Protein Dephosphorylation Protein phosphatase Proteins Research Resistance Series Signal Pathway Staphylococcus aureus Structure Structure-Activity Relationship Therapeutic Therapeutic Agents Validation Virulent Work analog antimicrobial base clinically relevant drug discovery enzyme activity high throughput screening human pathogen improved in vitro activity in vivo in vivo Model inhibitor microbial microbicide microorganism miniaturize mortality novel therapeutics pathogen pathogenic bacteria pathogenic fungus pathogenic microbe response small molecule small molecule inhibitor translational impact

项目摘要

PROJECT SUMMARY The Sts phosphatases negatively regulate signaling pathways within cells of the mammalian immune system. Mice lacking Sts expression (Sts-/-) are profoundly resistant to infection by clinically relevant fungal and bacterial pathogens, including Candida albicans, Francisella tularensis, and Staphylococcus aureus. Resistance is associated with rapid pathogen clearance and reduced inflammation. Our preliminary data demonstrates that phagocytes lacking Sts expression have enhanced microbicidal functions. We have shown that the Sts phosphatase domain is structurally and mechanistically distinct from other classes of protein phosphatases. We also demonstrate that the Sts active site sits in a distinct binding pocket, and enzyme activity can be competitively inhibited with drug-like compounds. We hypothesize that drug-mediated inhibition of Sts-1 will recapitulate the Sts-/- phenotype and lead to beneficial clinical outcomes. Based on this hypothesis, the objective of this proposal is to identify and characterize small molecule inhibitors of Sts-1 that can enhance leukocyte anti-microbial responses and demonstrate efficacy in whole animal infection models. To achieve this objective, we will conduct a high-throughput screen (HTS) of the 530K compound Scripps Drug Discovery Library. Active compounds will be extensively characterized and thoroughly validated, using our established assays and in vivo models. We will accomplish our objective by completing the following Specific Aims: Specific Aim 1: Conduct a 530K compound HTS to identify inhibitors of Sts-1 phosphatase activity. Specific Aim 2: Validate and characterize hit compounds. Specific Aim 3: Determine the effects of Sts inhibitory compounds on host responses to microbial infection. Successful completion of the proposed studies will yield a set of validated small molecule inhibitors of Sts phosphatase activity that will serve both as chemical probes of function and as leads for the development of novel therapeutic agents. In the long term, this work is expected to provide a foundation for the development of new clinical protocols that will significantly reduce the morbidity and mortality attributed to systemic pathogen infections, by enhancing host immune responses.

项目总结 Sts磷酸酶负向调节哺乳动物免疫细胞内的信号通路系统。缺乏Sts表达的小鼠(Sts-/-)对临床相关真菌的感染具有深刻的抵抗力以及细菌病原体，包括白色念珠菌、图拉氏弗朗西斯菌和金黄色葡萄球菌。耐药性与病原体迅速清除和炎症减少有关。我们的初步数据表明缺乏Sts表达的吞噬细胞具有增强的杀菌功能。我们已经证明，Sts磷酸酶结构域在结构和机制上都与其他蛋白质磷酸酶的种类。我们还证明了Sts活性位点位于不同的结合中 Pocket，酶活性可与类药物化合物竞争抑制。我们假设药物介导的抑制Sts-1将概括Sts-/-表型并导致有益的临床结果。基于这一假设，这一提议的目标是识别和描述小的可增强白细胞抗微生物反应并显示疗效的Sts-1分子抑制剂在整个动物感染模型中。为了实现这一目标，我们将进行高通量筛选 (HTS)的530K化合物斯克里普斯药物发现文库。活性化合物将广泛应用于使用我们已建立的分析方法和体内模型，对其进行了表征和彻底验证。我们将通过完成以下具体目标来实现目标：具体目标1：进行530K的化合物HTS以确定Sts-1磷酸酶活性的抑制剂。具体目标2：验证和表征HIT化合物。具体目标3：确定Sts抑制化合物对宿主对微生物反应的影响感染。拟议研究的成功完成将产生一套经过验证的Sts小分子抑制剂磷酸酶活性，既可以作为功能的化学探针，也可以作为发育的先导新的治疗药物。从长远来看，这项工作有望为开发新的临床方案，将显著降低因以下原因引起的发病率和死亡率全身性病原体感染，通过增强宿主免疫反应。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery and Characterization of Two Classes of Selective Inhibitors of the Suppressor of the TCR Signaling Family of Proteins.

TCR 信号蛋白家族抑制剂的两类选择性抑制剂的发现和表征。

DOI：
10.1021/acsinfecdis.8b00238
发表时间：
2019
期刊：
ACS infectious diseases
影响因子：
5.3
作者：
Zhou,Weijie;Yin,Yue;Smith,Emery;Chou,Jacqueline;Shumate,Justin;Scampavia,Louis;Spicer,TimothyP;Carpino,Nicholas;French,JarrodB
通讯作者：
French,JarrodB

The Sts Proteins: Modulators of Host Immunity.

STS蛋白质：宿主免疫的调节剂。