Carbohydrate epitope discovery via chemical synthesis

通过化学合成发现碳水化合物表位

• 批准号: 10549645
• 负责人: PAUL B SAVAGE
• 金额: $ 21.23万
• 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/10549645
• 关键词: Adjuvant; Affinity; Antibiotics; Antibodies; Antibody Affinity; Antigens; Aspartate; B-Lymphocytes; Bacteria; Bacterial Infections; Binding; Carbohydrates; Cell Wall; Clupeidae; Companions; Complement; Complement Activation; Dangerousness; Development; Dimensions; Disease Outbreaks; Drug resistance; Enzymes; Epitopes; Family; Fimbriae Proteins; Generations; Growth; Health; Hospitals; Human; Hypertension; Immune Evasion; Immune response; Immune system; Immunity; Immunoglobulin Class Switching; Immunoglobulin M; Individual; Infection; Infectious Agent; Instruction; Investigation; Klebsiella Infections; Klebsiella pneumoniae; Label; Learning; Link; Methods; Natural Immunity; Nature; Neisseria gonorrhoeae; Oligosaccharides; Organism; Outcomes Research; Peptides; Performance; Phagocytosis; Polymers; Polysaccharides; Polyvalence; Preparation; Process; Production; Reagent; Resistance; Scientist; Serine; Serotyping; Staphylococcus aureus; Structure; System; T-Cell Receptor; T-Lymphocyte; Therapeutic Uses; Time; Trisaccharides; United States National Institutes of Health; Vaccines; Virus; Virus-like particle; Work; adaptive immunity; chemical synthesis; design; drug resistant bacteria; fighting; glycosylation; human pathogen; nanomolar; novel therapeutics; pathogen; pathogenic bacteria; pressure; resistant strain; response; ribulose; sugar

Abstract The human immune system is capable of eliminating nearly any type of infectious agent; however, in many cases it must be “instructed” how to recognize specific pathogens. Bacteria have evolved means of evading aspects of immunity by cloaking themselves in polymeric sugars (glycans), and the first interactions between bacteria and the immune system involve these glycans. While this cloaking mechanism can protect bacteria from potent immune responses, it can also be an exploitable weakness. Our collaborative group, borrowing on work from many pioneering scientists, has developed means of using this cloaking mechanism to “instruct” the immune system to selectively target specific types of bacteria. In this Project, we are preparing the specific instructions for adaptive immunity, which will result in production of highly specific antibodies for the targeted bacteria. The targeted bacteria include some of the most prevalent and dangerous human pathogens, including drug-resistant Staphylococcus aureus, Klebsiella pneumoniae and Neisseria gonorrhoeae. In this project, we are investigating how antibodies recognize specific sections of the polymeric glycans produced by bacteria. This investigation involves preparation of individual sections of the glycans, comprised of two, three or four sugars. From these sections, vaccines will be generated that will trigger production of high-affinity antibodies for each individual section. These antibodies will be evaluated for how well they bind to the polymeric glycan and to intact bacteria and how well these antibodies function in promoting elimination the targeted bacteria by the immune system. From information generated by the study of the performance of antibodies generated to specific sections of the polymeric glycan, we will learn which portions of the glycan can be bound by antibodies and how large of section provides the strongest and most selective binding. Outcomes of this research include an understanding the size and nature of bacterial glycans that can be used for vaccine generation and for the development of high-affinity antibodies that will provide a means of treating bacterial infections.

抽象的 人类免疫系统能够消除几乎任何类型的感染剂。但是，在许多情况下 必须“指示”如何识别特定病原体。细菌发展了逃避方面的手段 通过在聚合物糖（Glycans）和细菌之间的第一次相互作用中掩盖免疫力 免疫系统涉及这些聚糖。虽然这种掩盖机制可以保护细菌免受有效的影响 免疫反应，这也可能是可剥削的弱点。我们的合作小组，从 许多开创性的科学家已经开发了使用这种掩护机制来“指导”免疫的方法 选择性靶向特定类型细菌的系统。在这个项目中，我们正在准备特定说明 为了自适应免疫，这将导致产生针对靶向细菌的高度特异性抗体。 靶向细菌包括一些最普遍和危险的人类病原体，包括抗药性 金黄色葡萄球菌，肺炎克雷伯菌和淋病奈瑟氏菌。在这个项目中，我们正在调查 抗体如何识别细菌产生的聚合物聚糖的特定切片。这项调查 涉及制备聚糖的各个部分，由两，三个或四个糖组成。从这些 将生成部分，将生成疫苗，以触发每个人的高亲和力抗体的产生 部分。这些抗体将被评估，以评估它们与聚合物聚糖的结合程度和完整的细菌 这些抗体在通过免疫系统促进靶向细菌方面的作用。 根据研究对特定部分生成的抗体的性能产生的信息 聚合物聚糖，我们将了解聚糖的哪些部分可以受抗体的约束以及部分的大小 提供强大，最选择性的结合。这项研究的结果包括了解大小 和可用于疫苗生成和高亲和力发展的细菌糖的性质 将提供一种治疗细菌感染方法的抗体。