Laboratory Syntheses of Mycobacterial tuberculosis LAM Prototypes

描述(申请人提供)：结核病在经过几十年的控制后--至少在第一世界国家--正在令人不安地卷土重来，其菌株被证明是多药耐药(MDR)，最近又出现了广泛耐药(XDR)。几十年来效果如此之好的卡介苗已经不再可靠了。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。负责任的结核分枝杆菌在一定程度上受到低聚糖堡垒的保护，低聚糖的免疫调节亚域是脂阿拉伯甘露聚糖(LAM)。除了结核病，LAM还被证明与各种疾病有关，如疱疹、膀胱癌、艾滋病毒、过敏性哮喘和I型糖尿病。由于结核分枝杆菌的毒力，一直无法确定其LAM的确切结构，但通过对毒力较低的分枝杆菌的结构研究，已经拼凑出了“起作用的”漫画。尽管存在这些结构上的不确定性，但生物学作用已被分配给不同的亚域，特别是一个被称为“帽”的可变成分。我们的实验室从各种卡通中提取信息，以获得LAM原型的工作合成目标，并在国家科学基金会的资助下，我们能够探索相关的方法学。初步工作中概述的出色进展预示着LAM原型的合成工作即将完成。 与公共卫生相关：寡糖、寡核苷酸和寡肽构成了生物过程中涉及的三种低聚物，尽管最后两种已经屈服于常规的实验室合成，但第一种仍然面临着令人生畏的挑战。在国家科学基金会的一项题为“告诉糖基捐赠者去哪里”的资助下，PI和他的同事们制定了克服许多障碍的策略，并通过实现被称为脂阿拉伯甘露聚糖(LAM)的复杂免疫调节寡糖糖脂(LAM)的主要结构域的首次实验室合成证明了其有效性。它固定在分枝杆菌物种的外细胞壁上，特别是结核分枝杆菌。LAM是一种化学堡垒的一部分，它可以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完全合成的完成，这将为开发治疗剂提供毫无疑问的真实性材料。

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.