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

描述（申请人提供）：幽门螺杆菌（Hp）是世界范围内引起十二指肠溃疡和胃炎的主要原因。不幸的是，现有的抗生素经常不能根除Hp感染并治愈这些疾病。对Hp发病机制的深入了解将极大地帮助开发新的治疗方法。Hp的毒力似乎与病原体对糖基化蛋白的能力直接相关。尽管Hp可以合成大量的糖蛋白，但尚不清楚的是这些糖蛋白中哪些参与了宿主-病原体的相互作用，如何利用它们来治疗慢性Hp感染，以及它们是否可以选择性地靶向。该项目的长期目标是利用化学的力量，使细菌糖基化的基础研究成为可能，特别是在人类疾病方面。本应用程序的目的是鉴定可作为药物靶点的Hp糖蛋白，开发基于其独特聚糖灭活Hp的策略，并评估我们针对Hp的靶向策略比其他细菌的选择性。中心假设

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.