Structural Biology Core

项目摘要/摘要 细菌对抗生素的耐药性是一个主要的全球健康威胁。我们的建议旨在发展 免疫疗法的重点是细菌表面的糖链，作为一种潜在的范式转变 与威胁生命的细菌作斗争，目前对这些细菌的治疗选择有限。我们的目标是 开发基于抗体的新型疫苗和抗体疗法，以帮助满足不断发展的 这些细菌带来的挑战。这笔赠款将特别侧重于开发和开发 四种糖链和糖肽的抗体和MHC II类的特性 三种生物的衣壳抗原、肽多聚糖、磷壁酸和O-连接的多聚糖： 金黄色葡萄球菌(Sa)、肺炎克雷伯菌(Kp)、淋病奈瑟菌(Ng)。这个 糖链抗原将被呈递给免疫系统，与多肽相连，并与 在类似病毒的颗粒上化学定义的位置。 结构生物学核心3将利用高通量X射线结晶学 艺术工具、仪器和设施，用于从结构和生物物理上表征被引诱的人 与用于免疫的多糖形成复合体的抗体。此外，我们还将审查 MHC II类分子与设计的糖肽的复合物，以探索这些独特的 结构呈现给T细胞。我们的结构结果将用于指导迭代回合的 对具有项目1-4和核心1，2的抗原、连接物和多肽进行修饰，以聚焦和 增强对这些具有挑战性的目标的免疫反应。这些结构还将引导 利用项目4和核心2设计抗体以提高其治疗潜力。 研究将通过行政核心进行协调。

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.