Deciphering Helicobacter pylori's glycocode: uncovering & harnessing drug targets

破译幽门螺杆菌的糖码：揭秘

• 批准号: 8771584
• 负责人: Danielle H. Dube
• 金额: $ 28.9万
• 依托单位: BOWDOIN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771584
• 关键词: Acids; Affect; Anti-Bacterial Agents; Antibiotics; Area; Bacteria; Bacterial Infections; Binding; Biology; Cells; Chemistry; Chronic; Data; Development; Disease; Drug Targeting; Duodenal Ulcer; Engineering; Flagella; Flagellin; Gastritis; Glycobiology; Glycoproteins; Goals; Helicobacter Infections; Helicobacter pylori; Human; Knowledge; Label; Laboratories; Lead; Link; Measures; Membrane Glycoproteins; Metabolic; Mission; Modification; Monosaccharides; Oligosaccharides; Outcome; Pathogenesis; Patients; Polysaccharides; Proteins; Public Health; Reporter; Reporting; Research; Specificity; Staging; Surface; Testing; Therapeutic; Therapeutic Intervention; Ulcer; Virulence; Work; base; glycosylation; human disease; innovation; insight; novel; overexpression; pathogen; public health relevance; sugar; therapeutic target

DESCRIPTION (provided by applicant): Helicobacter pylori (Hp) is the leading cause of duodenal ulcers and gastritis worldwide. Unfortunately, existing antibiotics frequently fail to eradicate Hp infection and cure these ailments. The development of new treatments will be greatly aided by insights into the pathogenesis of Hp. Virulence of Hp appears to be directly linked to the pathogen's ability to glycosylate proteins. Although Hp synthesizes a vast array of glycoproteins, what is not clear is which of these species are involved in host-pathogen interactions, how they can be harnessed to treat chronic Hp infection, and if they can be targeted selectively. The long-term goal of this project is to harness the power of chemistry to enable fundamental studies of bacterial glycosylation, particularly with respect to human disease. The objectives of this application are to identify Hp glycoproteins that could serve as drug targets, to develop a strategy to inactivate Hp based on its distinctive glycans, and to assess the selectivity of our targeting strategy for Hp over other bacteria. The central hypothesis of the application is that Hp's glycoproteins are involved in host-pathogen interactions, can serve as targets for covalent delivery of therapeutics, and can be selectively targeted without broadly interfering with most bacteria. Our hypothesis has been formulated on the basis of strong preliminary data produced in my laboratory, including the demonstration that a subset of Hp's surface glycoproteins are overexpressed in the presence of host cells. Further, my laboratory has reported that therapeutic probes can be covalently delivered to surface glycans on Hp. Finally, my lab has demonstrated that metabolic labeling of glycans is not uniform across bacterial species, thus setting the stage for selective targeting of glycans only found on pathogens. The rationale for the proposed research is that novel targets of therapeutic intervention will be revealed, resulting in new and innovative approaches to treat bac- terial disease. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Identify Hp glycoproteins involved in host-pathogen interactions; 2) Develop therapeutics that target Hp's surface glycans; and 3) Assess the selectivity of our targeting strategy for Hp. Under the first aim, the importance of Hp's glycoproteins in binding to host cells will be evaluated, and an already proven approach will be used to identify Hp glycoproteins that are preferentially overexpressed in the presence of host cells. Under the second aim, metabolically labeled glycans on Hp's surface will be targeted with therapeutics, and then the damage to Hp will be measured. Under the third aim, the incorporation of azidosugars onto surfaces of pathogenic and symbiotic bacteria will be evaluated, and the selectivity of targeting Hp with covalent therapeutics will be analyzed. The proposed research is innovative because it will lead to a targeted antibacterial strategy that has the potential to treat Hp infection while minimizing the effects on other bacteria, a substantive departure from the status quo. This contribution is significant because it is an important step in a continuum of research that is expected to lead to development of glycosylation-based strategies to treat ulcers and gastritis.

描述（由申请人提供）：幽门螺杆菌（Hp）是全世界十二指肠溃疡和胃炎的主要原因。不幸的是，现有的抗生素常常无法根除幽门螺杆菌感染并治愈这些疾病。对幽门螺杆菌发病机制的深入了解将极大有助于新疗法的开发。 Hp 的毒力似乎与病原体糖基化蛋白质的能力直接相关。尽管 Hp 合成大量糖蛋白，但尚不清楚哪些物种参与了宿主与病原体的相互作用，如何利用它们来治疗慢性 Hp 感染，以及是否可以选择性地靶向它们。该项目的长期目标是利用化学的力量来进行细菌糖基化的基础研究，特别是在人类疾病方面。本申请的目的是识别可作为药物靶点的 Hp 糖蛋白，开发基于其独特聚糖的灭活 Hp 的策略，并评估我们针对 Hp 的靶向策略相对于其他细菌的选择性。中心假设 该应用的主要特点是，Hp 的糖蛋白参与宿主与病原体的相互作用，可以作为治疗药物共价传递的靶标，并且可以选择性地靶向而不广泛干扰大多数细菌。我们的假设是根据我的实验室产生的强有力的初步数据制定的，包括证明 Hp 表面糖蛋白的一个子集在宿主细胞存在的情况下过度表达。此外，我的实验室报告说，治疗探针可以共价传递到 Hp 的表面聚糖上。最后，我的实验室证明，聚糖的代谢标记在不同细菌物种中并不统一，从而为选择性靶向仅在病原体上发现的聚糖奠定了基础。拟议研究的基本原理是，将揭示治疗干预的新目标，从而产生治疗细菌性疾病的新方法和创新方法。在强有力的初步数据的指导下，这一假设将通过三个具体目标进行检验：1）鉴定参与宿主-病原体相互作用的Hp糖蛋白； 2) 开发针对 Hp 表面聚糖的治疗方法； 3) 评估我们针对 Hp 的目标策略的选择性。第一个目标是 Hp 糖蛋白与宿主细胞结合的重要性 将进行评估，并且将使用一种已经经过验证的方法来识别在宿主细胞存在的情况下优先过度表达的 Hp 糖蛋白。在第二个目标下，Hp 表面代谢标记的聚糖将成为治疗的目标，然后测量对 Hp 的损害。第三个目标将评估叠氮糖在病原菌和共生菌表面的掺入，并分析共价疗法靶向 Hp 的选择性。拟议的研究具有创新性，因为它将产生一种有针对性的抗菌策略，有可能治疗幽门螺杆菌感染，同时最大限度地减少对其他细菌的影响，这与现状有实质性的不同。这一贡献意义重大，因为它是连续研究中的重要一步，预计将导致开发基于糖基化的治疗溃疡和胃炎的策略。