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.

摘要 人类免疫系统能够消除几乎任何类型的感染因子;然而，在许多情况下， 必须“指导”它如何识别特定的病原体。细菌进化出了逃避 免疫系统的免疫性通过将自己隐藏在聚合糖（聚糖）中，以及细菌之间的第一次相互作用， 而免疫系统也与这些聚糖有关。虽然这种隐形机制可以保护细菌免受强大的 免疫反应，它也可以是一个可利用的弱点。我们的合作小组，借鉴了 许多先驱科学家已经开发出利用这种隐形机制来“指导”免疫系统的方法， 系统选择性地针对特定类型的细菌。在本项目中，我们正在编写具体说明， 用于获得性免疫，这将导致产生针对目标细菌的高度特异性抗体。的 目标细菌包括一些最流行和最危险的人类病原体，包括耐药性 金黄色葡萄球菌、肺炎克雷伯菌和淋病奈瑟菌。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聚糖的特定部分。这次调查 包括制备由两种、三种或四种糖组成的聚糖的各个部分。从这些 将产生疫苗，这将触发每个个体产生高亲和力抗体 科.将评价这些抗体与多聚聚糖和完整细菌的结合情况 以及这些抗体在促进免疫系统消除目标细菌方面的功能如何。 从研究所产生的抗体的性能所产生的信息中， 我们将了解聚糖的哪些部分可以被抗体结合，以及聚糖的大小。 提供最强和最有选择性的结合。这项研究的结果包括了解 和性质的细菌聚糖，可用于疫苗的生产和发展的高亲和力 抗体将提供治疗细菌感染的方法。