Activated Sugars, Oligosaccharides and Glycans for Antiviral Research

用于抗病毒研究的活性糖、低聚糖和聚糖

基本信息

批准号：
10405128
负责人：
Leila Aminova
金额：
$ 86.8万
依托单位：
MIDWEST BIOPROCESSING CENTER, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405128
关键词：
2019-nCoV ACE2 Adhesions Anti-Infective Agents Antiviral Agents Binding Biology Bioreactors Candida Catalogs Cells Clinical Complex Custom Cytidine Monophosphate N-Acetylneuraminic Acid Dengue Development Directed Molecular Evolution Engineering Enzymes Epitopes Feasibility Studies Fucose Galactose Binding Lectin Glucose Glycobiology Glycoproteins Goals Grant Guanosine Diphosphate Fucose Guanosine Diphosphate Mannose HIV Infections Haemophilus influenzae type b Hepatitis C Human Human Milk Immunity Infection Link Mannose Masks Membrane Proteins Methods Modeling Natural Immunity Nature Neisseria meningitidis Neuraminidase Oligosaccharides Parasites Pathology Phase Plasmodium Play Polysaccharides Price Production Property Protein Glycosylation Proteins Reagent Research Research Personnel Research Support Role Sialic Acids Streptococcus pneumoniae System T-Lymphocyte Technology Uridine Diphosphate Galactose Vaccine Research Vaccines Viral Virus Virus Receptors Work antiviral drug development assay development betacoronavirus chitobiose feasibility research fungus galactokinase glycosylation inhibitor large scale production novel novel therapeutics pathogenic bacteria receptor research and development scale up stem success sugar sugar nucleotide thermostability

项目摘要

SUMMARY The goal of this project is to develop novel methods to produce sugar building blocks, oligosaccharides, and glycans needed to support and grow R&D related to viral glycobiology at large scale and reasonable prices. This technology will support researchers studying viral pathology, analyses of viral binding and interactions with hosts, studies to develop novel antiviral therapeutics and vaccines, and others. Glycobiology is important in a number of ways for viral research. Viral surface proteins are often heavily glycosylated to both avoid recognition by the host cell and, in some cases, interact with host receptors. For example, the spike protein glycosylation of the SARS-CoV-2 virus is usually the extension of an N-linked core pentasaccharide compound, composed of a stem of chitobiose followed by mannoses to form two antennary complexes. Understanding glycosylation of viral spike proteins and their potential epitope masking is of fundamental importance for vaccine research. Receptors recognized by many viruses are glycosylated proteins as well. SARS-CoV-2 and others uses angiotensin-converting enzyme 2, (ACE2) as its receptor, and other b-coronaviruses, utilize sialic acid residues on cellular glycoproteins as receptors. Glycans are currently being studied as vaccines against viruses (Dengue, Hepatitis C), parasites (Plasmodium) and fungi (Candida). Human milk oligosaccharides (HMOs) have been shown to reduce the possibility of infections due to interference with adhesion of pathogenic bacteria and potentially viruses. Galectins have been shown have pro- or anti-viral properties and play important role in innate immunity. Finally, some galectin inhibitors may block HIV infection of T cells. Oligosaccharides are currently isolated from nature or synthesized at extremely low yield via a complex set of protection and deprotection steps. Oligosaccharides and the activated sugar building blocks needed to build them enzymatically are needed in larger quantities to support and spawn additional research in this important field. In the Feasibility study we successfully demonstrated the development of a set of novel enzymes to produce a wide range of key activated sugar building blocks required to build important oligosaccharides. We then demonstrated the use of these activated sugars to extend model oligosaccharide chains. In the Phase II work, we will increase the scale of production of all of these activated sugars, extend the system to produce additional activated sugars needed, and make a number of key oligosaccharides important to viral biology research. Products made during the Phase II Research will be distributed to investigators and in Phase III products will be commercialized as part of our research reagent catalog or by carrying out custom synthesis of oligosaccharides for third parties.

概括该项目的目标是开发生产糖结构单元、低聚糖、和聚糖需要大规模且合理地支持和发展与病毒糖生物学相关的研发价格。该技术将支持研究人员研究病毒病理学、病毒结合分析和与宿主的相互作用、开发新型抗病毒疗法和疫苗的研究等。糖生物学在病毒研究的许多方面都很重要。病毒表面蛋白往往大量糖基化以避免被宿主细胞识别，并且在某些情况下与宿主受体相互作用。为了例如，SARS-CoV-2病毒的刺突蛋白糖基化通常是N连接核心的延伸五糖化合物，由壳二糖茎和甘露糖组成，形成两个天线复合物。了解病毒刺突蛋白的糖基化及其潜在的表位掩蔽至关重要对于疫苗研究具有根本重要性。许多病毒识别的受体都是糖基化的蛋白质也是如此。 SARS-CoV-2等使用血管紧张素转换酶2（ACE2）作为其受体，并且其他b-冠状病毒利用细胞糖蛋白上的唾液酸残基作为受体。目前正在研究聚糖作为病毒（登革热、丙型肝炎）、寄生虫的疫苗（疟原虫）和真菌（念珠菌）。母乳低聚糖（HMO）已被证明可以减少由于干扰病原菌和潜在病毒的粘附而导致感染的可能性。半乳糖凝集素已被证明具有促病毒或抗病毒特性，并在先天免疫中发挥重要作用。最后，一些半乳糖凝集素抑制剂可能会阻止 HIV 对 T 细胞的感染。目前已分离出低聚糖来自自然界或通过一系列复杂的保护和脱保护步骤以极低的产率合成。需要低聚糖和酶促构建它们所需的活性糖构建块更大的数量来支持和催生这一重要领域的更多研究。在可行性研究中，我们成功地展示了一套新型酶的开发生产构建重要寡糖所需的各种关键活性糖构建块。我们然后演示了使用这些活化糖来延长模型寡糖链。在第二阶段工作中，我们将增加所有这些活性糖的生产规模，扩展生产系统需要额外的活化糖，并使许多关键寡糖对病毒生物学变得重要研究。第二阶段研究期间生产的产品将分发给研究人员，第三阶段研究期间生产的产品将分发给研究人员产品将作为我们研究试剂目录的一部分或通过进行定制合成来商业化第三方低聚糖。