Laboratory Syntheses of Mycobacterial tuberculosis LAM Prototypes

结核分枝杆菌 LAM 原型的实验室合成

• 批准号: 7626500
• 负责人: Bertram Oliver Fraser-Reid
• 金额: $ 5.49万
• 依托单位: NATURAL PRODUCTS/GLYCOTECHNOLOGY RES INS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626500
• 关键词: Acids; BCG Vaccine; Bacteria; Biological; Biological Process; Cartoons; Cell Wall; Chemicals; Complex; Diagnosis; Disease; Extreme drug resistant tuberculosis; Extrinsic asthma; Foundations; Funding; Future; Genus Mycobacterium; Glycolipids; Grant; HIV; HIV Infections; Inositol; Insulin-Dependent Diabetes Mellitus; Laboratories; Lipids; Malignant neoplasm of urinary bladder; Mannans; Methodology; Multi-Drug Resistance; Mycobacterium tuberculosis; Oligonucleotides; Oligopeptides; Oligosaccharides; Pharmaceutical Preparations; Polysaccharides; Role; Scheme; Science; Structure; Therapeutic Agents; Translating; Tuberculosis; Uncertainty; Virulence; Virulent; Work; abstracting; araban; lipoarabinomannan; mycobacterial; prototype; public health relevance

DESCRIPTION (provided by applicant): Tuberculosis, after several decades of control - at least in First World nations - is seeing a troubling resurgence, with strains that are proving to be multi-drug resistant (MDR) and, of late, extensively drug resistant (XDR). The BCG vaccine that worked so well for decades is no longer reliable. Synergy with HIV infection provides a looming, dismal prospect. The responsible agent, Mycobacterium tuberculosis, is protected, in part, by a fortress of oligosaccharides, an immunomodulatory sub-domain of which is lipoarabinomannan (LAM). In addition to TB, LAMs have been shown to be associated with diseases as varied as herpes, bladder cancer, HIV, allergic asthma and type I diabetes. Because of the virulence of M. tuberculosis, it has been impossible to assign the exact structure of its LAM, but "working" cartoons have been cobbled together from structural studies on less virulent mycobacteria. In spite of these structural uncertainties, biological roles have been assigned to the various sub-domains, notably, a variable component known as the "cap". Our lab has distilled information from various cartoons to obtain a working synthetic target of a LAM prototype, and with funding from the National Science Foundation, we have been able to explore relevant methodologies. Excellent progress, outlined in the preliminary work, augurs well for completing syntheses of LAM prototypes PUBLIC HEALTH RELEVANCE:Oligosaccharides, oligonucleotides and oligopeptides constitute the three oligomers that are implicated in biological processes, but while the last two have yielded to regular laboratory synthesis, the first continues to present daunting challenges. Under a grant from the National Science Foundation entitled "Telling glycosyl donors where to go" the PI and coworkers have developed strategies to overcome many of the obstacles, and have demonstrated validity by achieving the first laboratory syntheses of major domains of the complex immunoregulatory oligosaccharide glycolipid, known as a lipoarabinomannan (LAM). which is anchored to the external cell wall of Mycobacterial species, notably M. tuberculosis. LAM is part of a chemical fortress that protects the bacterium from external agents such as drugs, thereby inhibiting cures as well as diagnosis. Our preliminary synthetic work augurs well for completion of a total synthesis of LAM that will provide material of unquestioned authenticity for use in developing therapeutic agents.

描述（由申请人提供）：结核病，经过几十年的控制-至少在第一世界国家-正在看到一个令人不安的复苏，与菌株被证明是多药耐药（MDR），最近，广泛耐药（XDR）。几十年来效果很好的卡介苗不再可靠。与艾滋病毒感染的协同作用提供了一个隐约可见的、令人沮丧的前景。负责代理，结核分枝杆菌，是保护，在一定程度上，由堡垒的寡糖，免疫调节子域的脂阿拉伯甘露聚糖（LAM）。除结核病外，LAMs还与疱疹、膀胱癌、HIV、过敏性哮喘和I型糖尿病等多种疾病有关。由于M.结核分枝杆菌中，不可能确定其LAM的确切结构，但“工作”漫画已经从毒性较低的分枝杆菌的结构研究中拼凑出来。尽管存在这些结构上的不确定性，生物学作用已被分配给各个子域，特别是称为“帽”的可变组分。我们的实验室已经从各种漫画中提取了信息，以获得LAM原型的工作合成目标，并且在美国国家科学基金会的资助下，我们已经能够探索相关的方法。出色的进展，概述了初步工作，预示着很好地完成合成的LAM原型 公共卫生相关性：寡核苷酸、寡核苷酸和寡肽构成了生物过程中涉及的三种寡聚物，但尽管后两种寡聚物已被常规实验室合成所取代，但前一种寡聚物仍面临着艰巨的挑战。在国家科学基金会题为“告诉糖基供体去哪里”的资助下，PI和同事们开发了克服许多障碍的策略，并通过实现复杂免疫调节寡糖糖脂（称为脂阿拉伯甘露聚糖（LAM））的主要结构域的首次实验室合成证明了有效性。其锚定在分枝杆菌物种，特别是M.结核LAM是化学堡垒的一部分，保护细菌免受药物等外部因素的影响，从而抑制治疗和诊断。我们的初步合成工作预示着LAM的全合成的完成，这将为开发治疗剂提供毫无疑问的真实性材料。