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.

概括 该项目的目的是开发新的方法来生产糖的基础，寡糖， 以及需要大规模且合理地支持与病毒性糖生物学有关的聚糖 价格。该技术将支持研究病毒病理学，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。 糖生物学在许多方面进行病毒研究很重要。病毒表面蛋白通常很重 糖基化既避免宿主细胞识别，又在某些情况下与宿主受体相互作用。为了 例如，SARS-COV-2病毒的尖峰蛋白糖基化通常是N连接核的延伸 五糖化合物，由壳聚糖茎组成 复合物。了解病毒尖峰蛋白的糖基化及其潜在的表位掩蔽是 对于疫苗研究的基本重要性。许多病毒识别的受体是糖基化的 蛋白质也是如此。 SARS-COV-2和其他人使用血管紧张素转换酶2，（ACE2）作为其受体，并且 其他B-核纳病毒利用细胞糖蛋白上的唾液酸残基作为受体。 目前正在将糖作为针对病毒的疫苗（登革热，丙型肝炎），寄生虫 （疟原虫）和真菌（念珠菌）。人牛奶寡糖（HMO）已显示可减少 由于干扰致病细菌和潜在病毒而引起的感染的可能性。 甲状腺激素已显示为促病毒特性，并在先天免疫中起重要作用。 最后，一些甲状腺蛋白抑制剂可能会阻断T细胞的HIV感染。目前孤立的寡糖 通过一组复杂的保护和脱身步骤，从自然或以极低的收率合成。 需要在 在这个重要领域支持和产生更多研究的大量数量。 在可行性研究中，我们成功证明了一组新型酶的发展 产生建造重要的寡糖所需的广泛的钥匙激活糖块。我们 然后证明使用这些活化的糖来扩展模型的寡糖链。在第二阶段 工作，我们将增加所有这些激活糖的生产规模，扩展系统以生产 需要其他活化的糖，并使许多关键的寡糖对病毒生物学重要 研究。在第二阶段研究期间生产的产品将分配给研究人员和第三阶段 产品将作为我们的研究试剂目录的一部分进行商业化，或通过执行自定义合成 第三方的寡糖。