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

• 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
• 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

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.

总结 该项目的目标是开发新的方法来生产糖结构单元，低聚糖， 和聚糖，以支持和发展大规模和合理的病毒糖生物学相关研发。 价格这项技术将支持研究人员研究病毒病理学，分析病毒结合， 与宿主的相互作用，开发新的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。病毒表面蛋白质通常 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 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 一种五糖化合物，由壳二糖茎和甘露糖组成，形成两个触角 配合物了解病毒刺突蛋白的糖基化及其潜在的表位掩蔽是 对疫苗研究至关重要。许多病毒识别的受体是糖基化的 蛋白质也是。SARS-CoV-2和其他病毒使用血管紧张素转换酶2（ACE2）作为其受体， 其它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抗病毒（登革热、丙型肝炎）、寄生虫 （疟原虫）和真菌（念珠菌）。人乳低聚糖（HMO）已被证明可以减少 由于干扰致病菌和潜在病毒的粘附而可能感染。 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以阻断T细胞的HIV感染。寡聚体目前被分离出来 从自然界或通过一组复杂的保护和脱保护步骤以极低的产率合成。 酶促构建它们所需的寡聚体和活化的糖结构单元是必需的， 更大的数量，以支持和促进在这一重要领域的额外研究。 在可行性研究中，我们成功地证明了一套新酶的开发， 生产广泛的关键活性糖构建模块所需的建立重要的寡糖。我们 然后证明使用这些活化糖来延长模型寡糖链。ii期 工作，我们将增加所有这些活性糖的生产规模，扩大系统，以生产 需要额外的活化糖，并使许多关键寡糖对病毒生物学很重要 research.第二阶段研究期间制造的产品将分发给研究者，并在第三阶段进行 产品将作为我们研究试剂目录的一部分商业化，或通过进行定制合成， 第三方的低聚糖。