Novel broad spectrum therapeutic glycans against Category B pathogens

针对 B 类病原体的新型广谱治疗聚糖

基本信息

批准号：
7934513
负责人：
DAVID S. NEWBURG
金额：
$ 89.03万
依托单位：
BOSTON COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7934513
关键词：
Address Adhesions Animals Bacteria Binding Biomedical Engineering Calicivirus Campylobacter Campylobacter jejuni Categories Cell surface Cells Chemicals Consumption Data Diarrhea Diet Epidemic Epidemiologic Studies Epitopes Escherichia coli Exposure to Family Force of Gravity Generations Glycoconjugates Human Human Milk In Vitro Individual Infection Infection prevention Inflammatory Response Intestinal Mucosa Lead Link Methods Molecular Molecular Weight Mucin-1 Staining Method Mucins National Institute of Allergy and Infectious Disease Norovirus Oligosaccharides Oral Pathogenesis Phase Plants Polysaccharides Population Populations at Risk Pre-Clinical Model Preclinical Testing Production Research Resistance Resistance development Severities Staging Structure Taste Perception Techniques Temperature Testing Therapeutic Therapeutic Agents Therapeutic Uses Vibrio Vibrio cholerae Virus Yeasts analog antimicrobial drug biodefense cost design drinking human disease in vivo inhibitor/antagonist instrument large scale production microorganism novel novel therapeutics pathogen pathogen exposure polylactosamine prebiotics preclinical study prevent prophylactic prototype quantum receptor scale up success

项目摘要

DESCRIPTION (provided by applicant): The glycans (oligosaccharides and glycoconjugates) of human milk are powerful pathogen anti-adhesion compounds, and represent a novel class of antimicrobial agents. We propose to synthesize and test two of the most promising prototypes of fucosyl glycans (oligosaccharides and mucin) that naturally occur in human milk and have been shown, from in vitro, in vivo and molecular epidemiologic studies, to strongly inhibit NIAID Category B pathogens Campylobacter, Vibrio cholera, diarrheagenic Escherichia coli, and caliciviruses (noroviruses). These glycans function as receptor analogs that prevent infection by inhibiting pathogen binding to host cell surface glycans. Further, repeated pathogen exposure to such glycans does not result in resistance. Such glycans are stable for prolonged periods at room temperature, are intrinsically pleasant tasting, and could be produced and distributed economically as part of a drink or nutriment to individuals or populations at risk. A major roadblock to preclinical studies and human trials, however, has been the complexity and cost of synthesis of these fucosyl glycans. We propose to use recent breakthroughs in bioengineering for two generations of large-scale synthesis of fucosyl glycans in genetically modified microorganisms. Fucosyl oligosaccharides expressed in a bacterial construct will serve as standard synthetic monovalent inhibitors. A simultaneous but longer second generation of synthesis will be construction of a yeast that produces high molecular weight mucins whose polyvalent and multivalent expression of fucosylated moieties are expected to provide stronger and more broadly effective pathogen inhibition. The synthesis of these fucosyl glycans and their preclinical testing would be a quantum step towards a novel family of broadly effective therapeutics and prophylactics, would bring us to the threshold of human trials against Category B pathogens, and would represent a powerful new instrument for biodefense.

描述（由申请人提供）：母乳中的聚糖（低聚糖和复合糖）是强大的病原体抗粘连化合物，代表了一类新型抗菌剂。我们建议合成和测试两种最有前途的岩藻糖基聚糖原型（低聚糖和粘蛋白），它们天然存在于母乳中，体外、体内和分子流行病学研究表明，它们可以强烈抑制 NIAID B 类病原体弯曲杆菌、霍乱弧菌、致腹泻性大肠杆菌和杯状病毒（诺如病毒）。这些聚糖充当受体类似物，通过抑制病原体与宿主细胞表面聚糖的结合来预防感染。此外，病原体反复暴露于此类聚糖不会导致耐药性。此类聚糖在室温下可长时间保持稳定，本质上味道宜人，并且可以经济地生产和分配，作为饮料或营养品的一部分提供给处于危险中的个人或人群。然而，临床前研究和人体试验的主要障碍是这些岩藻糖基聚糖合成的复杂性和成本。我们建议利用生物工程的最新突破，在转基因微生物中进行两代大规模岩藻糖基聚糖合成。在细菌构建体中表达的岩藻糖基寡糖将充当标准的合成单价抑制剂。同时但更长的第二代合成将构建产生高分子量粘蛋白的酵母，其岩藻糖基化部分的多价和多价表达预计将提供更强和更广泛有效的病原体抑制。这些岩藻糖基聚糖的合成及其临床前测试将是迈向广泛有效的治疗和预防新家族的重要一步，将使我们迈向针对 B 类病原体的人体试验的门槛，并将代表一种强大的生物防御新工具。