Synthesis and Evaluation of Zwitterionic Carbohydrate Immunostimulants

两性离子碳水化合物免疫增强剂的合成与评价

• 批准号: 9109179
• 负责人: Hien M Nguyen
• 金额: $ 18.66万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109179
• 关键词: Address; Adjuvant; Aluminum Hydroxide; Antibodies; Antigen-Presenting Cells; Antigens; Bacterial Infections; Bacteroides fragilis; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Carbohydrates; Charge; Chemistry; Circular Dichroism; Clinical; Communicable Diseases; Development; Dose; Evaluation; Event; Galactose; Generations; Glycoconjugates; Goals; Haptens; Health; Human; Immune response; Immunity; Immunologic Adjuvants; Immunology; Iowa; Isomerism; Methodology; Microbiology; Molecular Conformation; Mus; Nickel; Oligosaccharides; Organic solvent product; Polysaccharides; Process; Production; Regulation; Research Personnel; Role; Safety; Salts; Signal Transduction; Source; Structure; Structure-Activity Relationship; T cell response; T-Lymphocyte; Tetanus Toxoid; Toxic effect; Tumor-Associated Carbohydrate Antigens; Universities; Vaccination; Vaccine Adjuvant; Vaccines; Variant; aluminum phosphate; aluminum sulfate; analog; base; biphenyl hydrolase-related protein; chemical synthesis; clinically relevant; combat; cytokine; glycosylation; immune function; immunogenic; immunogenicity; improved; in vivo; mouse model; novel vaccines; preclinical evaluation; public health relevance; research study; response; success; tool; tumor

 DESCRIPTION (provided by applicant): Although the use of vaccines to combat infectious diseases has greatly improved human health, they are poorly immunogenic and requires multiple doses for protection. As such, vaccines are co-administered with an adjuvant to enhance immunity. Numerous classes of vaccine adjuvants have been developed and showed the desired immune response over the past several decades. Unfortunately, only a few adjuvants are considered to be sufficiently potent and clinically liable for use in humans. Alum, a mixture of aluminum hydroxide and phosphate salts, remains the dominant adjuvant with extensive safety record approved for use in human vaccination. In efforts to discover new adjuvants, an unusual class of carbohydrates, zwitterionic polysaccharides (ZPSs), containing both negative and positive charge motifs in their repeating units, were found to activate CD4+ T-cell-dependent immune responses and modulate host cytokine responses to bacterial infection. ZPSs when co-administered with antigen tetanus toxoid increase the specific antibody tier, illustrating their capacity to serve as potential vaccine adjuvants in vivo. One of the best characterized ZPSs is zwitterionic polysaccharide PS A1, isolated from capsular Bacteroides fragilis. Studies showed that glycoconjugates, generated from conjugation of PS A1 to tumor-associated mucin antigen TN, elicits high titer antibodies that are specific and selective for the TN hapten. Despite the promise of PS A1 as a potential adjuvant, obtaining it from natural sources is a complicated process of extraction and purification that results in the production of minute, relatively impure quantities and could alter its structure. Since FDA has strict regulation regarding the purity and quality of vaccine adjuvants for use in humans, a synthetic source must be developed for PS A1 to be utilized as a clinically relevant adjuvant. The main goal of this proposal will address these challenges through the chemical synthesis of natural and non-natural PS A1 oligosaccharides with defined repeating units utilizing our recently developed nickel-catalyzed α-glycosylation methodologies. This proposed effort will deliver defined PS A1 molecules in high purity without batch-to-batch variation and provide tools for studying their roles as adjuvants and exploring structure-relationship activity (SAR) studies. 1

 描述（由申请人提供）：虽然使用疫苗来对抗传染病极大地改善了人类健康，但它们的免疫原性较差并且需要多次剂量才能提供保护，因此，疫苗与佐剂共同施用以增强免疫力。在过去的几十年里，已经开发出多种疫苗佐剂并显示出所需的免疫反应，但遗憾的是，只有少数佐剂被认为具有足够的效力并且在临床上对明矾（一种明矾）敏感。 氢氧化铝和磷酸盐的混合物，仍然是主要的佐剂，具有广泛的安全记录，被批准用于人类疫苗接种。研究发现，当与破伤风抗原共同给药时，它们的重复单元可以激活 CD4+ T 细胞依赖性免疫反应并调节宿主细胞因子对细菌感染的反应。类毒素增加了特异性抗体层，说明其在体内作为潜在疫苗佐剂的能力是两性离子多糖 PS A1，它是从荚膜脆弱拟杆菌中分离出来的。研究表明，糖缀合物是由 PS A1 与肿瘤结合而产生的。 -相关粘蛋白抗原 TN，引发对 TN 半抗原具有特异性和选择性的高滴度抗体，尽管有 PS A1 的前景。作为一种相对有潜力的佐剂，从天然来源获取它是一个复杂的提取和纯化过程，导致产量极少、不纯，并且可能会改变其结构，因为 FDA 对所使用的疫苗佐剂的纯度和质量有严格的规定。在人类中，必须开发一种合成来源，将 PS A1 用作临床相关佐剂。该提案的主要目标是通过利用我们的化学合成具有确定重复单元的天然和非天然 PS A1 寡糖来解决这些挑战。最近开发了镍催化 α-糖基化方法，这项工作将提供高纯度的确定的 PS A1 分子，且不会出现批次间的差异，并为研究其作为佐剂的作用和探索结构关系活性 (SAR) 研究提供工具1。