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 人体免疫系统能够消除几乎所有类型的传染源。然而，在很多情况下 必须“指导”它如何识别特定的病原体。细菌已经进化出逃避方面的手段 通过将自身包裹在聚合糖（聚糖）中来实现免疫力，以及细菌之间的首次相互作用 免疫系统涉及这些聚糖。虽然这种隐形机制可以保护细菌免受强力侵害 免疫反应，它也可能是一个可利用的弱点。我们的协作小组借鉴了 许多先驱科学家已经开发出利用这种隐藏机制来“指导”免疫系统的方法 系统选择性地针对特定类型的细菌。在这个项目中，我们正在准备具体的说明 用于适应性免疫，这将导致针对目标细菌产生高度特异性的抗体。这 目标细菌包括一些最普遍和最危险的人类病原体，包括耐药细菌 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，我们正在研究 抗体如何识别细菌产生的聚合聚糖的特定部分。此次调查 涉及制备由两种、三种或四种糖组成的聚糖的各个部分。从这些 部分，将产生疫苗，这将触发每个人产生高亲和力抗体 部分。将评估这些抗体与聚合聚糖和完整细菌的结合程度 以及这些抗体在促进免疫系统消除目标细菌方面的作用如何。 从抗体性能研究产生的信息中生成到特定部分 聚合聚糖，我们将了解聚糖的哪些部分可以被抗体结合以及部分有多大 提供最强且最具选择性的结合。这项研究的成果包括了解规模 可用于疫苗生成和高亲和力开发的细菌聚糖的性质和性质 抗体将提供治疗细菌感染的方法。