Novel broad spectrum therapeutic glycans against Category B pathogens

描述(由申请人提供)： 人乳中的低聚糖和糖偶联物是一类新型的抗菌剂，具有很强的抗细菌粘附性。我们建议合成和测试两个最有希望的岩藻糖基多糖原型(低聚糖和粘蛋白)，这两个原型自然存在于母乳中，体外、体内和分子流行病学研究表明，它们对NIAID B类病原体弯曲杆菌、霍乱弧菌、致腹泻大肠杆菌和杯状病毒(诺如病毒)有很强的抑制作用。这些多糖作为受体类似物发挥作用，通过抑制病原体与宿主细胞表面多糖的结合来防止感染。此外，病原体反复接触这种多聚糖不会产生抗药性。这种多糖在室温下可以长时间稳定，是一种本质上令人愉悦的味道，可以作为饮料或营养的一部分经济地生产和分发给处于危险之中的个人或人群。然而，临床前研究和人体试验的一个主要障碍是这些岩藻糖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合成岩藻糖聚糖。在细菌构建中表达的岩藻糖寡糖将作为标准的合成单价抑制剂。同时但更长的第二代合成将是构建一种产生高分子粘蛋白的酵母，其多价和多价岩藻糖化部分的表达有望提供更强和更广泛的病原体抑制。这些岩藻糖基多糖的合成和临床前试验将是朝着广泛有效的治疗和预防药物的新家族迈出的一大步，将把我们带到针对B类病原体的人体试验的门槛，并将代表着一种强大的生物防御新工具。

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.