Activated Sugars for Drug Discovery

用于药物发现的活化糖

• 批准号: 7849708
• 负责人: Leila Aminova
• 金额: $ 36.19万
• 依托单位: ZUCHEM, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849708
• 关键词: Address; Antibiotic Resistance; Antibiotics; Arabinose; Bacteria; Biochemical; Biological; Biological Factors; Carbohydrates; Coupled; Coupling; Crystallization; Economics; Engineering; Enzymes; Escherichia coli; Galactose; Gel Chromatography; Goals; Hand; High Pressure Liquid Chromatography; In Vitro; Ion Exchange; Libraries; Mannose; Methods; Natural regeneration; Nucleotides; Oligosaccharides; Pharmacologic Substance; Phase; Phosphotransferases; Polyphosphate kinase; Polyphosphates; Positioning Attribute; Process; Production; Property; Protein Engineering; Reaction; Recovery; Recycling; Research; Research Project Grants; Ribose; Specificity; Stereoisomer; Substrate Specificity; System; Technology; Testing; Therapeutic; Time; Toxic effect; Transferase; Vancomycin; Work; Xylose; Xylulose; combinatorial; directed evolution; drug discovery; enzyme immobilization; glycosylation; glycosyltransferase; gulose; improved; inorganic phosphate; interest; lyxose; monomer; new technology; novel; novel therapeutics; nucleotidyltransferase; programs; public health relevance; research and development; ribulose; scale up; small molecule; sugar

DESCRIPTION (provided by applicant): The overall goal of this proposal is to create a robust one pot, in vitro, multi-gram scale synthesis of activated sugars for drug discovery and biochemical research purposes. Natural product glycosylation is vital for the discovery of new pharmaceutical compounds. While it has been recognized for some time that many biologically active natural products owe much of their therapeutic properties to their glycosylation diversity, methods for creating further diversity for drug discovery have been difficult to develop. One of the challenges is that the modified and rare sugars needed for creating diversity are unavailable or extremely difficult to make, and that the sugars need to be chemically "activated" in order to transfer them to the core natural product molecule. However, new technology has been developed where a chemoenzymatic method is used to attach sugars to natural production aglycons. With this method, a combination of a kinase and nucleotide transferase are needed to form the specific activated sugar and finally a glycosyltransferase is used to transfer the sugar to an appropriate aglycon core. This technology is valuable for drug discovery, as it can be used to produce a library of differentially glycosylated natural product molecules. The Phase II research of this project will continue the improvements in the enzymes needed for this process, including engineering a greater substrate range. The research will then focus on coupling the best enzymes, ATP/NTP regeneration, product recovery, process scale-up and creating novel antibiotic derivatives as a demonstration of the developed technology. PUBLIC HEALTH RELEVANCE: This project is aimed toward developing a method for making a variety of activated sugars for drug discovery purposes. These sugars can used to make derivatives of natural products with new therapeutic properties, for example, antibiotics that are effective against antibiotic-resistant bacteria.

描述（由申请人提供）：该提案的总体目标是创建一个坚固的一个锅，体外，多克度量表合成活化糖的药物发现和生化研究目的。天然产物糖基化对于发现新药物化合物至关重要。尽管一段时间以来，许多生物活跃的天然产品都归功于其糖基化多样性，但很难开发出进一步的药物发现多样性。挑战之一是，创造多样性所需的修改和稀有糖是不可用或极难制造的，并且需要对糖进行化学“激活”以将其转移到核心天然产物分子中。但是，已经开发了新技术，其中使用化学酶方法将糖固定在自然产生的aglycons上。使用这种方法，需要组合激酶和核苷酸转移酶来形成特定的活化糖，最后，使用糖基转移酶将糖转移到适当的AglyCon核心上。该技术对于药物发现很有价值，因为它可用于生产差异糖基化天然产物分子的库。该项目的第二阶段研究将继续改善此过程所需的酶，包括工程更大的底物范围。然后，这项研究将重点介绍最佳酶，ATP/NTP再生，产品恢复，过程扩大，并创建新型的抗生素衍生物，以证明已发达的技术。公共卫生相关性：该项目旨在开发一种用于制造用于药物发现目的的激活糖的方法。这些糖可以用来使天然产物的衍生物具有新的治疗特性，例如，抗生素有效抗生素耐药细菌。