Structural Biology Core

结构生物学核心

• 批准号: 10549644
• 负责人: IAN A WILSON
• 金额: $ 36.2万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549644
• 关键词: Acceleration; Affinity; Anti-Bacterial Agents; Antibodies; Antibody Specificity; Antigens; B-Lymphocytes; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Binding; Biochemical; Biophysics; CD4 Positive T Lymphocytes; Charge; Chemicals; Complex; Development; Dimensions; Engineering; Fab Immunoglobulins; Glycopeptides; Goals; Grant; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Immune response; Immune system; Immunization; Immunologics; Immunotherapy; Klebsiella pneumoniae; Length; Life; Link; MHC Class II Genes; Mission; Modeling; Modification; Neisseria gonorrhoeae; Organism; Peptides; Peptidoglycan; Polysaccharides; Site; Staphylococcus aureus; Structure; Surface; T cell response; T-Lymphocyte; Teichoic Acids; Therapeutic; Therapeutic antibodies; Vaccines; Virus-like particle; X-Ray Crystallography; antibody engineering; biophysical properties; design; efficacy testing; fighting; global health; improved; instrumentation; novel; rational design; response; structural biology; tool

PROJECT SUMMARY / ABSTRACT Bacterial antibiotic resistance is a major global health threat. Our proposal aims to develop immunotherapies focused on the surface glycans of bacteria as a potential paradigm shift in the fight against life-threatening bacteria, for which current therapeutic options are limited. We aim to develop novel antibody-based vaccines and antibody therapeutics to help meet the evolving challenge presented by these bacteria. In particular, the grant will focus on developing and characterizing antibodies and MHC class II to four classes of glycans and glycopeptides from the capsular antigens, peptidoglycans, teichoic acids and O-linked glycans from three organisms: Staphylococcus aureus (Sa), Klebsiella pneumoniae (Kp), and Neisseria gonorrhea (Ng). The glycan antigens will be presented to the immune system linked to peptides and conjugated to chemically defined sites on virus-like particles. The Structural Biology Core 3 will utilize high-throughput x-ray crystallography with state-of-the art tools, instrumentation and facilities to structurally and biophysically characterize the elicited antibodies in complex with the glycans used for immunization. In addition, we will examine complexes of MHC Class II molecules with designed glycopeptides to explore how these unique structures are presented to T cells. Our structural results will be used to guide iterative rounds of modifications to the antigens, linkers and peptides with Projects 1-4 and Cores 1,2 to focus and enhance the immune response to these challenging targets. The structures will also guide in the engineering of antibodies to improve their therapeutic potential with Project 4 and Core 2. All studies will be coordinated through the Administrative Core.

项目总结/摘要 细菌抗生素耐药性是一个主要的全球健康威胁。我们的建议旨在发展 免疫疗法集中在细菌的表面聚糖上，作为免疫疗法的潜在范式转变。 对抗威胁生命的细菌，目前的治疗选择有限。我们的目标是 开发新型抗体疫苗和抗体疗法，以帮助满足不断发展的 这些细菌带来的挑战。特别是，赠款将侧重于发展和 将抗体和MHC II类表征为四类聚糖和糖肽， 来自三种生物体的荚膜抗原、肽聚糖、磷壁酸和O-连接聚糖： 金黄色葡萄球菌（Sa）、肺炎克雷伯菌（Kp）和淋病奈瑟菌（Ng）。的 聚糖抗原将被呈递给免疫系统， 病毒样颗粒上的化学定义位点。 结构生物学核心3将利用高通量X射线晶体学， 艺术工具，仪器和设施，以结构和生物药理学特征的诱发 与用于免疫的聚糖复合的抗体。此外，我们将研究 MHC II类分子与设计的糖肽的复合物，以探索这些独特的 结构被呈递给T细胞。我们的结构结果将用于指导迭代轮的 重点关注项目1-4和核心1、2对抗原、接头和肽的修饰， 增强对这些具有挑战性的目标的免疫反应。这些结构还将指导 工程抗体，以提高其与项目4和核心2的治疗潜力。所有 研究将通过行政核心进行协调。