ORAL CANDIDASIS: ANTIGEN STRUCTURE AND VACCINE DESIGN

口腔念珠菌病：抗原结构和疫苗设计

• 批准号: 6286200
• 负责人: ROBERT J WOODS
• 金额: $ 25.77万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-29 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6286200
• 关键词: Candida albicans; X ray crystallography; biomimetics; biotechnology; candidiasis; carbohydrate structure; chemical models; chemical structure function; computer simulation; drug design /synthesis /production; drug screening /evaluation; fungal antigens; fungal vaccines; laboratory mouse; molecular dynamics; nuclear magnetic resonance spectroscopy; synthetic peptide; vaccine development

The goal of this proposal is to develop and evaluate the efficacy of anti-Candida vaccines for use in the treatment of oropharyngeal Candidiasis (OPC). To achieve optimal design, the applicants will take a purely synthetic approach to vaccine synthesis. The immunogenic core of the vaccine is based on recently discovered peptides that are able to elicit protective anti-Candida responses in mice. These peptides were found by screening antibodies, raised against the cell surface polysaccharides of C. albicans, against a phage-displayed peptide library. To enhance the immunogenicity of the peptides, they will be covalently linked to a branched dendrimer, which will also contain a linked lipid adjuvant. This approach will enable the applicants to precisely vary the valency of the vaccine molecules and thereby optimize their immunogenicity. The details of the mechanism through which the immunogenic peptides are able to mimic the endogenous carbohydrate epitope are unknown. This mimicry is not an isolated example. Several peptides have now been reported that are capable of mimicking carbohydrates from a variety of sources. In general, this mimicry can be both immunological and structural. To date, however, very little is known about the physical nature of this mimicry. In order to exploit fully the peptide mimetics in the design of a vaccine, it is essential to better understand the structures of the peptides and the mechanism of the molecular mimicry. Therefore, concurrent with the chemical synthesis and immunological evaluations, they will attempt to determine the 3-dimensional structures of the free and antibody-bound forms of the carbohydrate epitope and the peptide mimetics. The structural information will be provided by three complementary techniques, namely, nuclear magnetic resonance (NMR) spectroscopy, X-ray diffraction analysis, and molecular modeling. Insight into the antigenic conformations of the peptides and endogenous antigens will provide a model for the further design and optimization of anti-Candida vaccines.

这项提案的目标是开发和评估 口咽念珠菌病治疗中使用的抗念珠菌疫苗 (OPC)。为了实现最佳设计，申请者将采用纯合成的 疫苗合成的方法。疫苗的免疫原性核心是基于 最近发现的能够诱导保护性抗念珠菌的多肽 小鼠的反应。这些多肽是通过筛选抗体发现的，提高了 抗白念珠菌细胞表面多糖，抗A 噬菌体展示多肽文库。为了增强多肽的免疫原性， 它们将共价连接到支化的树枝状大分子上，树枝状大分子也含有 一种连接的脂类佐剂。这种方法将使申请者能够准确地 改变疫苗分子的价态，从而优化它们的 免疫原性。免疫原性通过的机制的细节 多肽是否能够模拟内源性碳水化合物的表位尚不清楚。 这种模仿并不是孤立的例子。现在已经有几种多肽 据报道，它们能够模仿来自各种来源的碳水化合物。 一般来说，这种模仿既可以是免疫性的，也可以是结构性的。到目前为止， 然而，人们对这种模仿的物理本质知之甚少。在……里面 为了在疫苗设计中充分利用多肽模拟物，它是 对更好地理解多肽的结构和机制是必不可少的 分子模仿术。因此，与化学合成和 免疫学评估，他们将尝试确定三维 碳水化合物表位的游离型和抗体结合型的结构 多肽模拟物。结构信息将由三个人提供 补充技术，即核磁共振(核磁共振) 光谱学、X射线衍射分析和分子模拟。洞察 多肽和内源性抗原的抗原构象将 为进一步设计和优化抗念珠菌药物提供了模型 疫苗。