Laboratory Syntheses of Mycobacterial tuberculosis LAM Prototypes

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——正在出现令人不安的死灰复燃，菌株被证明具有多重耐药（MDR）和最近的广泛耐药（XDR）。几十年来效果良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迫在眉睫的、令人沮丧的前景。负责的病原体结核分枝杆菌在一定程度上受到低聚糖堡垒的保护，低聚糖堡垒的免疫调节亚结构域是脂阿拉伯甘露聚糖（LAM）。除结核病外，lam已被证明与疱疹、膀胱癌、艾滋病毒、过敏性哮喘和I型糖尿病等多种疾病有关。由于结核分枝杆菌的毒性，确定其LAM的确切结构是不可能的，但是从毒性较弱的分枝杆菌的结构研究中拼凑出了“工作”图。尽管存在这些结构上的不确定性，生物学作用已被分配到不同的子结构域，特别是被称为“帽”的可变成分。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，并且在国家科学基金会的资助下，我们已经能够探索相关的方法。初步工作中概述的良好进展预示着完成LAM原型的合成

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.